Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e

Appendix II: Design and Optimization of Dosage Regimens: Pharmacokinetic Data

Kenneth E. Thummel; Danny D. Shen; Nina Isoherranen

INTRODUCTION

This appendix provides a summary of basic pharmacokinetic information pertaining to drugs that are in common clinical use and are delivered to the systemic circulation by parenteral or non-parenteral administration. Because of space limitations, this list cannot be exhaustive. Drugs designed exclusively for topical administration and not to be significantly absorbed into the bloodstream (e.g., ophthalmic and some dermal applications; Chapters 64 and 65) are not included. A few other selection criteria have influenced the makeup of the list, but, in general, the authors have tried to include one or more representative drugs in each of the therapeutic areas in this text, based on distinct mechanism(s) of action. In some instances, drugs may be excluded because pharmacokinetics are not relevant to their therapeutic management. An obvious case is when drug efficacy is not apparently correlated with drug concentration in a reversible fashion (e.g., some cytotoxic anticancer drugs). Also, for a number of therapeutic antibodies, the antibody is administered at a fixed dose at prolonged intervals that allows for its near complete clearance (e.g., infliximab).

Often, the issue comes down to deciding which of the many drugs within a class should be selected. This is particularly problematic when the choices are largely therapeutic equivalents. Two criteria that have proven useful are prevalence of use and uniqueness of mechanism of action. For the present edition, we have consulted the "2008 Top 200 Branded Drugs by Total Prescriptions" and "2008 Top 200 Generic Drugs by Total Prescriptions" published in the respective May 22 and 26, 2009, issues of Drug Topics (http://drugtopics.modernmedicine.com) for usage data. Drugs that fall into the top 200 list are selected. As mentioned above, a less used drug may be included if it has a different mechanism of action than the frequently used drugs, some additional actions that offer a unique therapeutic advantage, or a more acceptable side-effects profile.

Pharmacokinetic data for many older drugs not included in this appendix can be found in earlier editions of this book.

A major objective of this appendix is to present pharmacokinetic data in a format that informs the clinician of the essential characteristics of drug disposition that form the basis of drug-dosage regimen design. Table AII–1 contains quantitative information about the absorption, distribution, and elimination of drugs; the effects of disease states on these processes; and the correlation of efficacy and toxicity with drug concentrations in blood/plasma. The general principles that underlie the design of appropriate maintenance dose and dosing interval (and, where appropriate, the loading dose) for the average patient are described in Chapter 2. Their application using the data in Table AII–1 for individualization of dosage regimens is presented here.

To use the data that are presented, one must understand clearance concepts and their application to drug-dosage regimens. One also must know average values of clearance as well as some measures of the extent and kinetics of drug absorption and distribution. The text below defines the eight basic parameters that are listed in the tabular material for each drug and key factors that influence these values in both normal subjects and patients with renal or liver disease. It obviously would be more straightforward if there were a consensus on a standard value for a given pharmacokinetic parameter; instead, literature estimates usually vary over a wide range, and a consensus set of pharmacokinetic values has been reached for only a limited number of drugs.

In Table AII–1, a single set of values for each parameter and its variability in a relevant population has been selected from the literature, based on the scientific judgment of the authors. Most data are in the form of a study population mean value ± 1 standard deviation (mean ± SD). However, some data are presented as mean and range of values (in parentheses) observed for the study population (i.e., the lowest and highest value reported). There are times when data are reported as a geometric mean with a 95% confidence interval. If sufficient data were available, we presented a range of mean values obtained from different studies of similar design in parentheses, sometimes below the primary study data. Occasionally, only a single mean value for the study population was available in the literature and is reported as such. Finally, some drugs can be administered intravenously in an unmodified form and orally as a prodrug. When relevant information about both the prodrug and the active molecule are needed, we have included both, using an abbreviation to indicate the species that was measured, followed by another abbreviation in parentheses to indicate the species that was dosed [e.g., G (V) indicates a parameter for ganciclovir after administration of the prodrug, valganciclovir].

A number of recently approved drugs are actually the active metabolite or stereoisomer of a previously marketed drug. For example, desloratadine is the O-desmethyl metabolite of loratadine, and esomperazole is the active S-enantiomer of omeprazole. Unless the parent drug and the active metabolite offer distinct therapeutic advantages, only the more established or more commonly used drug is listed, and relevant information on its alternate active form is presented in the same table. This approach has permitted us to include more drugs in the Appendix, hopefully without undue confusion. The only exception is with prednisone and prednisolone, which undergo interconversion in the body.

Unless otherwise indicated in footnotes, data reported in the table are those determined in healthy adults. The direction of change for these values in particular disease states is noted below the average value. One or more references are provided for each of the established drugs, typically an original journal publication, a review on its clinical pharmacokinetics, or web-based drug database; the latter two secondary sources provide a broader range of papers for the interested reader. In some instances, we have relied on unpublished data provided by the drug sponsor in its New Drug Application (NDA) files or package labeling submitted to the U.S. Food and Drug Administration (FDA).

TABULATED PHARMACOKINETIC PARAMETERS

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Each of the eight parameters presented in Table AII–1 has been discussed in detail in Chapter 2. The following discussion focuses on the format in which the values are presented as well as on factors (physiological or pathological) that influence the parameters.

Bioavailability. The extent of oral bioavailability is expressed as a percentage of the administered dose. This value represents the percentage of the administered dose that is available to the systemic circulation—the fraction of the oral dose that reaches the arterial blood in an active or prodrug form, expressed as a percentage (0-100). Fractional availability (F), which appears elsewhere in this appendix, denotes the same parameter; this value varies from 0-1. Measures of both the extent and rate (see T_max) of availability are presented in the table. The extent of availability is needed for the design of an oral dosage regimen to achieve a specific target blood concentration. Values for multiple routes of administration are provided, when appropriate and available. In most cases, the tabulated value represents an absolute oral bioavailability that has been determined from a comparison of area under the plasma drug concentration–time curve (AUC) between the oral dose and an intravenous reference dose. For those drugs where intravenous administration is not feasible, an approximate estimate of oral bioavailability based on secondary information (e.g., urinary excretion of unchanged drug, especially when the nonrenal route of elimination is minimal) is presented, or the column is left blank (denoted by a long dash [—]). A dash also will appear when a drug is given by parenteral administration only.

A low bioavailability may result from a poorly formulated dosage form that fails to disintegrate or dissolve in the gastrointestinal fluid, degradative loss of drug in the gastrointestinal fluid, poor mucosal permeability, first-pass metabolism during transit through the intestinal epithelium, active efflux transport of drug back into the lumen, or first-pass hepatic metabolism or biliary excretion (see Chapter 2). In the case of drugs with extensive first-pass metabolism, hepatic disease may increase oral availability because hepatic metabolic capacity decreases and/or because vascular shunts develop around the liver.

Urinary Excretion of Unchanged Drug. The second parameter in Table AII–1 is the amount of drug eventually excreted unchanged in the urine, expressed as a percentage of the administered dose. Values represent the percentage expected in a healthy young adult (creatinine clearance ≥100 mL/min). When possible, the value listed is that determined after bolus intravenous administration of the drug, for which bioavailability is 100%. If the drug is given orally, this parameter may be underestimated due to incomplete absorption of the dose; such approximated values are indicated with a footnote. The parameter obtained after intravenous dosing is of greater utility because it reflects the relative contribution of renal clearance to total body clearance irrespective of bioavailability.

Renal disease is the primary factor that causes changes in this parameter. This is especially true when alternate pathways of elimination are available; thus, as renal function decreases, a greater fraction of the dose is available for elimination by other routes. Because renal function generally decreases as a function of age, the percentage of drug excreted unchanged also decreases with age when alternate pathways of elimination are available. In addition, for a number of weakly acidic and basic drugs with pK_a values within the normal range for urine pH, changes in urine pH will affect their rate or extent of urinary excretion (see Chapter 2).

Binding to Plasma Proteins. The tabulated value is the percentage of drug in the plasma that is bound to plasma proteins at concentrations of the drug that are achieved clinically. In almost all cases, the values are from measurements performed in vitro (rather than from ex vivo measurements of binding to proteins in plasma obtained from patients to whom the drug had been administered). When a single mean value is presented, it signifies that there is no apparent change in percent bound over the range of plasma drug concentrations resulting from the usual clinical doses. In cases in which saturation of binding to plasma proteins is approached within the therapeutic range of plasma drug concentrations, a range of bound percentages is provided for concentrations at the lower and upper limits of the range. For some drugs, there is disagreement in the literature about the extent of plasma-protein binding; in those cases, the range of reported values is given.

Plasma-protein binding is affected primarily by disease states, notably hepatic disease, renal failure, and inflammatory diseases, that alter the concentration of albumin, α₁-acid glycoprotein, or other proteins in plasma that bind drugs. Uremia also changes the binding affinity of albumin for some drugs. Disease-induced changes in plasma-protein binding can dramatically affect the volume of distribution, clearance, and elimination t_1/2 of a drug. In regard to clinical relevance, it is important to assess the change in unbound drug concentration or AUC, particularly when only unbound drug can cross biological barriers and gain access to the site of action.

Plasma Clearance. Systemic clearance of total drug from plasma or blood (see Equations 2–5 and 2–6) is given in Table AII–1. Clearance varies as a function of body size and, therefore, most frequently is presented in the table in units of mL/min/kg of body weight. Normalization to measures of body size other than weight may at times be more appropriate, such as normalization to body surface area in infants to better reflect the growth and development of the liver and kidneys. However, weight is easy to obtain, and its use often offsets any small loss in accuracy of clearance estimate, especially in adults. Exceptions to this rule are the anticancer drugs, for which dosage normalization to body surface area is conventionally used. When unit conversion was necessary, we used individual or mean body weight or body surface area (when appropriate) from the cited study, or if this was not available, we assumed a body mass of 70 kg or a body surface area of 1.73 m² for healthy adults.

In some cases, separate values for renal and nonrenal clearance are also provided. For some drugs, particularly those that are excreted predominantly unchanged in the urine, equations are given that relate total or renal clearance to creatinine clearance (also expressed as mL/min/kg). For drugs that exhibit saturation kinetics, K_m and V_max are given and represent, respectively, the plasma concentration at which half of the maximal rate of elimination is reached (in units of mass/volume) and the maximal rate of elimination (in units of mass/time/kg of body weight). K_m must be in the same units as the concentration of drug in plasma (C_p).

Intrinsic clearance from blood is the maximal possible clearance by the organ responsible for elimination when blood flow (delivery) of drug is not limiting. When expressed in terms of unbound drug, intrinsic clearance reflects clearance from intracellular water. Intrinsic clearance is tabulated for a few drugs. It also is mathematically related to the biochemical intrinsic clearance [V_max/(K_m + C)] determined in vitro. In almost all cases, clearances based on plasma concentration data are presented in Table AII–1, because drug analysis most often is performed on plasma samples. The few exceptions where clearance from blood is presented are indicated by footnote. Clearance estimates based on blood concentration may be useful when a drug concentrates in the blood cells.

To be accurate, clearances must be determined after intravenous drug administration. When only non-parenteral data are available, the ratio of CL/F is given; values offset by the fractional availability (F) are indicated in a footnote. When a drug, or its active isomer for racemic compounds, is a substrate for a cytochrome P450 (CYP) or drug transporter, this information is provided in a footnote. This information is important for understanding pharmacokinetic variability due to genetic polymorphisms and for predicting metabolically based drug-drug interactions.

Volume of Distribution. The total body volume of distribution at steady state (V_ss) is given in Table AII–1 and is expressed in units of L/kg or in units of L/m² for some anticancer drugs. Again, when unit conversion was necessary, we used individual or mean body weights or body surface area (when appropriate) from the cited study, or if such data were not available, we assumed a body mass of 70 kg or a body surface area of 1.73 m² for healthy adults.

When estimates of V_ss were not available, values for V_area were provided; V_area represents the volume at equilibrated distribution during the terminal elimination phase (see Equation 2–12). Unlike V_ss, V_area varies when drug elimination changes, even though there is no change in the distribution space. Because we may wish to know whether a particular disease state influences either the clearance or the tissue distribution of the drug, it is preferable to define volume in terms of V_ss, a parameter that is less likely to depend on changes in the rate of elimination. Occasionally, the condition under which the distribution volume was obtained was not specified in the primary reference; this is denoted by the absence of a subscript.

As with clearance, V_ss usually is defined in the table in terms of concentration in plasma rather than blood. Further, if data were not obtained after intravenous administration of the drug, a footnote will make clear that the apparent volume estimate, V_ss/F, is offset by the fractional availability.

Half-Life. Half-life (t_1/2) is the time required for the plasma concentration to decline by one-half when elimination is first order. It also governs the rate of approach to steady state and the degree of drug accumulation during multiple dosing or continuous infusion. For example, at a fixed dosing interval, the patient will be at 50% of steady state after one t_1/2, 75% of steady state after two half-lives, 93.75% of steady state after four half-lives, etc. Determination of t_1/2 is straightforward when drug elimination follows a monoexponential pattern (i.e., one-compartment model). However, for a number of drugs, plasma concentration follows a multiexponential pattern of decline over time. The mean value listed in Table AII–1 corresponds to an effective rate of elimination that covers the clearance of a major fraction of the absorbed dose from the body. In many cases, this t_1/2 refers to the rate of elimination in the terminal exponential phase. For a number of drugs, however, the t_1/2 of an earlier phase is presented, even though a prolonged t_1/2 may be observed at very low plasma concentrations when extremely sensitive analytical techniques are used. If the latter component accounts for ≤10% of the AUC, predictions of drug accumulation in plasma during continuous or repetitive dosing will be in error by no more than 10% if this longer t_1/2 is ignored. The clinician should know the t_1/2 that will best predict drug accumulation in the patient, which will be the appropriate t_1/2 to use for estimating the rate constant in Equations 1–19 through 1–21 (see Chapter 1) to predict time to steady state. It is this t_1/2 of accumulation during multiple dosing that is given in Table AII–1.

Half-life usually is independent of body size because it is a function of the ratio of two parameters, clearance and volume of distribution, each of which is proportional to body size. It also should be noted that the t_1/2 is preferably obtained from intravenous studies, if feasible, because the t_1/2 of decline in plasma drug concentration after oral dosing can be influenced by prolonged absorption, such as when slow release formulations are given. If the t_1/2 is derived from an oral dose, this will be indicated in a footnote of Table AII–1.

Time to Peak Concentration. Because clearance concepts are used most often in the design of multiple dosage regimens, the extent rather than the rate of availability is more critical to estimate the average steady-state concentration of drug in the body. In some circumstances, the degree of fluctuation in plasma drug concentration (i.e., peak and trough concentrations), which govern drug efficacy and side effects, can be greatly influenced by modulation of drug absorption rate through the use of sustained- or extended-release formulations. Controlled-release formulations often permit a reduction in dosing frequency from three or four times daily to once or twice daily. There also are drugs that are given on an acute basis (e.g., for the relief of breakthrough pain or to induce sleep), for which the rate of drug absorption is a critical determinant of onset of effect. Thus, information about the expected average time to achieve maximal plasma or blood concentration and the degree of interindividual variability in that parameter have been included in Table AII–1.

The time required to achieve a maximal concentration (T_max) depends on the rate of drug absorption into blood from the site of administration and the rate of elimination. From mass balance principles, T_max occurs when the rate of absorption equals the rate of elimination from the reference compartment. Prior to this time, absorption rate exceeds elimination rate, and the plasma concentration of drug increases. After the peak is reached, elimination rate exceeds the absorption rate and, at some point, defines the terminal elimination phase of the concentration-time profile.

The rate of drug absorption following oral administration will depend on the formulation and physicochemical properties of the drug, its permeability across the mucosal barrier, and the intestinal villous blood flow. For an oral dose, some absorption may occur very rapidly within the buccal cavity, esophagus, and stomach, or absorption may be delayed until the drug reaches the small intestine or until the local pH in the intestine permits drug release from the dosage formulation. In the most extreme case, the rate of absorption can be sufficiently controlled by the drug formulation to permit sustained or extended delivery as the dosage form traverses the entire length of the gastrointestinal tract. In some instances, the terminal elimination of drug from the body following a peak concentration reflects the slower rate of absorption and not elimination.

When more than one type of drug formulation is available commercially, we have provided absorption information for both the immediate- and sustained-release formulations. Not surprisingly, the presence of food in the gastrointestinal tract can alter both the rate and extent of drug availability. We have indicated with footnotes when the consumption of food near the time of drug ingestion may have a significant effect on the drug bioavailability.

Peak Concentration. There is no general agreement about the best way to describe the relationship between the concentration of drug in plasma and its effect. Many different kinds of data are present in the literature, and use of a single-effect parameter or effective concentration is difficult. This is particularly true for antimicrobial agents because the effective concentration depends on the identity of the microorganism causing the infection. It also is important to recognize that concentration-effect relationships are most easily obtained at steady state or during the terminal log-linear phase of the concentration-time curve, when the drug concentration(s) at the site(s) of action are expected to parallel those in plasma. Thus, when attempting to correlate a blood or plasma level to effect, the temporal aspect of distribution of drug to its site of action must be taken into account.

Despite these limitations, it is possible to define the minimum effective or toxic concentrations for some of the drugs currently in clinical use. However, in reviewing the list of drugs approved within the past 5 years, it is rare to find a declaration of an effective concentration range, even in the manufacturer's package labeling. Thus, it is necessary to infer therapeutic concentrations from concentrations observed following effective dosage regimens. For a given dosage regimen, a time-averaged steady-state blood or plasma concentration (i.e., C®_ss as estimated by dividing the mean AUC by the duration of the dosing interval) and the associated interindividual variability might be one appropriate parameter to report; however, such data often are not available. Also, C®_ss does not take into account the onset and offset of effect during fluctuation of plasma drug concentration over a dosing interval. In some instances, drug efficacy may be more closely linked with peak concentration than with the average or trough concentration, and differences in peak concentration for special populations (e.g., elderly) sometimes are associated with increased incidence of drug toxicity.

For practical reasons, the most commonly reported parameter, C_max (peak concentration), rather than effective or toxic concentrations, is presented in Table AII–1. This provides a more consistent body of information about drug exposure from which one can infer, if appropriate, efficacious or toxic blood levels. Although the value reported is the highest that would be encountered in a given dose interval, C_max can be related to the trough concentration (C_min) through appropriate mathematical predictions (see Equation 1–21). Because peak levels will vary with dose, we have attempted to present concentrations observed with a customary dose regimen that is recognized to be effective in the majority of patients. When a higher or lower dose rate is used, the expected peak level can be adjusted by assuming dose proportionality, unless nonlinear kinetics are indicated. In some instances, only limited data pertaining to multiple dosing are available, so single-dose peak concentrations are presented. When specific information is available about an effective therapeutic range of concentrations or about concentrations at which toxicity occurs, it has been incorporated in a footnote. For individual drugs, the reader also is referred to the index to locate pages where more detailed information is provided.

It is important to recognize that significant differences in C_max will occur when comparing similar daily-dose regimens for an immediate-release and sustained-release product. Indeed, the sustained-release product sometimes is administered to reduce peak-trough fluctuations during the dosing interval and to minimize swings between potentially toxic or ineffective drug concentrations. Again, we report C_max for both immediate- and extended-release formulations, when available. In addition to parent drug concentrations, we have included information on any active metabolite that circulates at a concentration that may contribute to the overall pharmacological effect, particularly those active metabolites that accumulate with multiple dosing. Likewise, for chiral drugs whose stereoisomers differ in their pharmacological activity and clearance characteristics, we present information on the levels of the individual enantiomers or the active enantiomer that contributes most to the drug's efficacy.

ALTERATIONS OF PARAMETERSIN THE INDIVIDUAL PATIENT

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Dose adjustments for an individual patient should be made according to the manufacturer's recommendation in the package labeling when available. This information generally is available when disease, age, or race has a significant impact on drug disposition, particularly for drugs that have been introduced within the past 10 years. In some cases, a significant difference in drug disposition from the "average" adult can be expected but may not require dose adjustment because of a sufficiently broad therapeutic index. In other cases, dose adjustment may be necessary, but no specific information is available. Under these circumstances, an estimate of the appropriate dosing regimen can be obtained based on pharmacokinetic principles described in Chapter 1.

Unless otherwise specified, the values in Table AII–1 represent mean values for populations of normal adults; it may be necessary to modify them for calculation of dosage regimens for individual patients. The fraction available (F) and clearance (CL) also must be estimated to compute a maintenance dose necessary to achieve a desired average steady-state concentration. To calculate the loading dose, knowledge of the volume of distribution is needed. The estimated t_1/2 is used in deciding a dosing interval that provides an acceptable peak-trough fluctuation; note that this may be the apparent t_1/2 following dosing of a slowly absorbed formulation. The values reported in the table and the adjustments apply only to adults; exceptions are footnoted. Although the values at times may be applied to children who weigh more than ∼30 kg (after proper adjustment for size; see "Clearance" and "Volume of Distribution" later), it is best to consult pediatrics textbooks or other sources for definitive advice.

For each drug, changes in the parameters caused by certain disease states are noted within the eight segments of the table. In all cases, the qualitative direction of changes is noted, such as "↓ LD," which indicates a significant decrease in the parameter in a patient with chronic liver disease. The relevant literature and the package label should be consulted for more definitive, quantitative information for dosage adjustment recommendations.

Plasma-Protein Binding. Most acidic drugs that are extensively bound to plasma proteins are bound to albumin. Basic lipophilic drugs, such as propranolol, often bind to other plasma proteins (e.g., α₁-acid glycoprotein and lipoproteins). The degree of drug binding to proteins will differ in pathophysiological states that cause changes in plasma-protein concentrations. Significant pharmacokinetic effects from a change in plasma-protein binding will be denoted under clearance or volume of distribution.

Although pharmacokinetic parameters based on total drug or metabolite concentrations often are reported, it is important to recognize that in many cases it is the concentration of unbound drug that drives access to the site of action and the degree of pharmacological effect. Remarkable changes in the total plasma concentration may accompany disease-induced alteration in protein binding; however, the clinical outcome is not always affected because an increase in free fraction also will increase the apparent clearance of an orally administered drug and of a low-extraction drug dosed intravenously. Under such a scenario, the mean unbound plasma concentration at steady state will not change with reduced or elevated plasma-protein binding, despite a significant change in mean total drug concentration. If so, no adjustment of daily maintenance dose is needed.

Clearance. For drugs that are partly or predominantly eliminated by renal excretion, plasma clearance changes in accordance with the renal function of an individual patient. This necessitates dosage adjustment that is dependent on the fraction of normal renal function remaining and the fraction of drug normally excreted unchanged in the urine. The latter quantity appears in the table; the former can be estimated as the ratio of the patient's creatinine clearance (CL_cr) to a normal value (100 mL/min/70 kg body weight). If urinary creatinine clearance has not been measured, it may be estimated from the concentration of creatinine in serum (C_cr). In men:

(Equation A-1)

For women, the estimate of CL_cr by the above equation should be multiplied by 0.85 to reflect their smaller muscle mass. The fraction of normal renal function (rfx_pt) is estimated from the following:

(Equation A-2)

A more accurate measure of rfx_pt seldom is necessary because, given the considerable degree of interindividual variation in nonrenal clearance, the adjustment of clearance is an approximation. The following equation for adjustment of clearance uses the quantities discussed:

(Equation A-3)

where fe_nl is the fraction of systemic drug excreted unchanged in normal individuals (see Table AII–1). The renal factor (rf_pt) is the value that, when multiplied by normal total clearance (CL_nl) from the table, gives the total clearance of the drug adjusted for the impairment in renal function.

Example. The clearance of vancomycin in a patient with reduced renal function (creatinine clearance = 25 mL/ min/70 kg) may be estimated as follows:

Importantly, such a clearance adjustment should be regarded only as an initial step in optimizing the dosage regimen; depending on the patient's response to the drug, further individualization may be necessary.

Conventionally, clearance is adjusted for the size of the patient to reflect a difference in the mass of the eliminating organ. For orally administered drugs, the applicability of such an adjustment may be limited by the available dosage strengths of commercial formulations. In some cases, scored tablets can be split, or commercial tablet splitters are used to increase the range of available dosage strengths. However, this practice should be followed only with the recommendation of the drug manufacturer because splitting a tablet sometimes can compromise the bioavailability of a product.

With the exception of certain oncolytic agents, the data presented in the table are normalized to weight. Thus, interindividual variability in the weight-normalized clearance reflects a variation in the intrinsic metabolic or transport clearance and not the size of the organ. Further, these differences can be attributed to variable expression/function of metabolic enzymes or transporters. However, it is important to recognize that liver mass and total enzyme/transporter content may not increase or decrease in proportion to weight in obese or malnourished individuals. Alternative approaches such as normalization by body surface area or other measures of body mass may be more appropriate. For example, many of the drugs used to treat cancer are dosed according to body surface area (see Chapter 51). In the tabulation, if the literature reported dose per body surface area, we presented the data in the same unit. If the cited clearance data were not normalized, but the preponderance of the literature utilized body surface area, we followed the practice of using values of body surface area from the literature source or a standard of 1.73 m² for a healthy adult.

Volume of Distribution. Volume of distribution should be adjusted for the modifying factors indicated in Table AII–1 as well as for body size. Again, the data in the table most often are normalized to weight. Unlike clearance, volume of distribution in an individual most often is proportional to weight itself. Whether this applies to a specific drug depends on the actual sites of distribution of drug; no absolute rule applies.

Whether or not to adjust volume of distribution for changes in binding to plasma proteins cannot be decided in general; the decision depends critically on whether or not the factors that alter binding to plasma proteins also alter binding to tissue proteins. Qualitative changes in volume of distribution, when they occur, are indicated in the table.

Half-Life. Half-life may be estimated from the adjusted values of clearance (CL_pt) and volume of distribution (V_pt) for the patient:

(Equation A-4)

Because t_1/2 has been the parameter most often measured and reported in the literature, qualitative changes for this parameter almost always are given in the table.

INDIVIDUALIZATION OF DOSAGE

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By using the parameters for the individual patient, calculated as described in the previous section, initial dosing regimens may be chosen. The maintenance dosage rate may be calculated with Equation 1–18, using the estimated values for CL and F for the individual patient. As described earlier, the target concentration may have to be adjusted for changes in plasma-protein binding in the patient, as described in "Plasma-Protein Binding." The loading dose may be calculated using Equation 1–22 and estimates for V_ss and F. A particular dosing interval may be chosen; the maximal and minimal steady-state concentrations can be calculated by using Equations 1–20 and 1–19 or 1–21, and these calculated concentrations can be compared with the known efficacious and toxic concentrations for the drug. As with the target concentration, these values may need to be adjusted for changes in the extent of plasma-protein binding. Use of Equations 1–19 and 1–20 also requires estimates of values for F, V_ss, and K (K = 0.693/t_1/2) for the individual patient.

Note that these adjustments of pharmacokinetic parameters for an individual patient are suggested for the rational choice of initial dosing regimen. As indicated in Chapter 1, steady-state measurement of drug concentrations in the patient then can be used as a guide to further adjust the dosage regimen. However, optimization of a dosage regimen for an individual patient ultimately will depend on the clinical response produced by the drug.

Table AII-1Pharmacokinetic Data

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Table AII-1 Pharmacokinetic Data

Key: Unless otherwise indicated by a specific footnote, the data are presented for the study population as a mean value ± 1 standard deviation, a mean and range (lowest-highest in parentheses) of values, a range of the lowest-highest values, or a single mean value. ACE, angiotensin-converting enzyme; ADH, alcohol dehydrogenase; Aged, aged; AIDS, acquired immunodeficiency syndrome; Alb, hypoalbuminemia; Alcohol, chronic consumption of ethanol; Atr Fib, atrial fibrillation; AVH, acute viral hepatitis; Burn, burn patients; C_max, peak concentration; CAD, coronary artery disease; Celiac, celiac disease; CF, cystic fibrosis; CHF, congestive heart failure; Child, children; COPD, chronic obstructive pulmonary disease; CP, cor pulmonale; CPBS, cardiopulmonary bypass surgery; CRI, chronic respiratory insufficiency; Crohn, Crohn's disease; Cush, Cushing's syndrome; CYP, cytochrome P450; F or Fem, female; Hep, hepatitis; HIV, human immunodeficiency virus; HL, hyperlipoproteinemia; HTh, hyperthyroid; IM, intramuscular; Inflam, inflammation; IV, intravenous; LD, chronic liver disease; LTh, hypothyroid; M, male; MAO, monoamine oxidase; MI, myocardial infarction; NAT, N-acetyltransferase; Neo, neonate; NIDDM, non-insulin-dependent diabetes mellitus; NS, nephrotic syndrome; Obes, obese; PDR54, Physicians' Desk Reference, 54th ed. Montvale, NJ, Medical Economics Co., 2000; PDR58, Physicians' Desk Reference, 58th ed. Montvale, NJ, Medical Economics Co., 2004; Pneu, pneumonia; PO, oral administration; Preg, pregnant; Prem, premature infants; RA, rheumatoid arthritis; Rac, racemic mixture of stereoisomers; RD = renal disease (including uremia); SC, subcutaneous; Smk, smoking; ST, sulfotransferase; T_max, peak time; Tach, ventricular tachycardia; UGT, UDP-glucuronosyl transferase; Ulcer, ulcer patients. Other abbreviations are defined in the text section of this appendix.

BioAVAILABILITY (ORAL) (%)

URINARY EXCRETION (%)

BOUND IN PLASMA (%)

CLEARANCE (mL/min/kg)

VOL. DIST. (L/kg)

HALF-LIFE (hours)

PEAK TIME (hours)

PEAK CONCENTRATION

Acetaminophen^a

88 ± 15

↔ Child

3 ± 1

↔ Neo, Child

<20

5.0 ± 1.4^b

↓ Hep^c

↔ Aged, Child

↑ Obes, HTh, Preg

0.95 ± 0.12^b

↔ Aged, Hep^c, LTh, HTh, Child

2.0 ± 0.4

↔ RD, Obes, Child

↑ Neo, Hep^c

↑ HTh, Preg

0.33–1.4^d

20 μg/mL^e

^aValues reported are for doses <2 g; drug exhibits concentration-dependent kinetics above this dose. ^bAssuming a 70-kg body weight; reported range, 65-72 kg. ^cAcetaminophen-induced hepatic damage or AVH. ^dAbsorption rate, but not extent, depends on gastric emptying; hence, it is slowed after food as well as in some disease states and co-treatment with drugs that cause gastroparesis. ^eMean concentration following a 20-mg/kg oral dose. Hepatic toxicity associated with levels >300 μg/mL at 4 hours after an overdose.

Reference: Forrest JA, et al. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet, 1982, 7:93–107.

Acetylsalicylic Acid^a

68 ± 3

↔ Aged, LD

1.4 ± 1.2

↓ RD

9.3 ± 1.1

↔ Aged, LD

0.15 ± 0.03

0.25 ± 0.03

↔ Hep

0.39 ± 0.21^b

24 ± 4 μg/mL^b

^aValues given are for unchanged parent drug. Acetylsalicylic acid is converted to salicylic acid during and after absorption (CL and t_1/2 of salicylate are dose dependent; t_1/2 varies between 2.4 hours after a 300-mg dose to 19 hours when there is intoxication). ^bFollowing a single1.2-g oral dose given to adults.

Reference: Roberts MS, et al. Pharmacokinetics of aspirin and salicylate in elderly subjects and in patients with alcoholic liver disease. Eur J Clin Pharmacol, 1983, 25:253–261.

Acyclovir

15-30^a

75 ± 10

15 ± 4

CL = 3.37CL_cr + 0.41

↓ Neo

↔ Child

0.69 ± 0.19

↑ Neo

↔ RD

2.4 ± 0.7

↑ RD, Neo

↔ Child

1.5-2^b

3.5-5.4 μM^b

^aDecreases with increasing dose. ^bRange of steady-state concentrations following a 400-mg dose given orally every 4 hours to steady state.

Reference: Laskin OL. Clinical pharmacokinetics of acyclovir. Clin Pharmacokinet, 1983, 8:187–201.

Albendazole^a

—^b

↑ Food

10.5-30.7^c

—

8 (6-15)^d

2-4^e

0.50-1.8 μg/mL^e

^aOral albendazole undergoes rapid and essentially complete first-pass metabolism to albendazole sulfoxide (ALBSO), which is pharmacologically active. Pharmacokinetic data for ALBSO in male and female adults are reported. ^bThe absolute bioavailability of ALBSO is not known but is increased by high-fat meals. ^cCL/F following twice-daily oral dosing to steady state. Chronic albendazole treatment appears to induce the metabolism of ALBSO. ^dt_1/2 reportedly shorter in children with neurocysticercosis compared with adults; may need to be dosed more frequently (three times a day) in children, rather than twice a day, as in adults. ^eFollowing a 7.5-mg/kg oral dose given twice daily for 8 days to adults.

References: Marques MP, et al. Enantioselective kinetic disposition of albendazole sulfoxide in patients with neurocysticercosis. Chirality, 1999, 11:218–223. PDR58, 2004, p. 1422. Sanchez M, et al. Pharmacokinetic comparison of two albendazole dosage regimens in patients with neurocysticercosis. Clin Neuropharmacol, 1993, 76:77–82. Sotelo J, et al. Pharmacokinetic optimisation of the treatment of neurocysticercosis. Clin Pharmacokinet, 1998, 34:503–515.

Albuterol^a

PO, R: 30 ± 7

PO, S: 71 ± 9

IH, R: 25

IH, S: 47

R: 46 ± 8

S: 55 ± 11

Rac: 7 ± 1

R: 10.3 ± 3.0

S: 6.5 ± 2.0

↓ RD^b

R: 2.00 ± 0.49

S: 1.77 ± 0.69

↓ RD^b

R: 2.00 ± 0.49

S: 2.85 ± 0.85

R: 1.5^c

S: 2.0^c

R: 3.6 (1.9-5.9) ng/mL^c

S: 11.4 (7.1-16.2) ng/mL^c

^aData from healthy subjects for R- and S-enantiomers. No major gender differences. No kinetic differences in asthmatics. β-Adrenergic activity resides primarily with R-enantiomer. PO, oral; IH, inhalation. Oral dose undergoes extensive first-pass sulfation at the intestinal mucosa. ^bCL/F reduced, moderate renal impairment. ^cMedian (range) following a single 4-mg oral dose of racemic-albuterol.

References: Boulton DW, et al. Enantioselective disposition of albuterol in humans. Clin Rev Allergy Immunol, 1996, 14:115–138. Mohamed MH, et al. Effects of gender and race on albuterol pharmacokinetics. Pharmacotherapy, 1999, 19:157–161.

Alendronate^a

<0.7^b

↓ Food

44.9 ± 9.3

1.11 (1.00-1.22)^c

↓ RD^d

0.44 (0.34-0.55)^c

∼1.0^e

IV: 2^f

IV: ∼275 ng/mL^f

PO: <5-8.4 ng/mL^f

^aData from healthy postmenopausal female subjects. ^bBased on urinary recovery; reduced when taken <1 hour before or up to 2 hours after a meal. ^cCL and V_ss values represent mean and 90% confidence interval. ^dMild to moderate renal impairment. ^eThe t_1/2 for release from bone is ∼11.9 years. ^fFollowing a single 10-mg IV infusion over 2 hours and a 10-mg oral dose daily for >3 years.

References: Cocquyt V, et al. Pharmacokinetics of intravenous alendronate. J Clin Pharmacol, 1999, 39:385–393. Porras AG, et al. Pharmacokinetics of alendronate. Clin Pharmacokinet, 1999, 36:315–328.

Alfentanil

—

92 ± 2

↓ Cirr

6.7 ± 2.4^a

↓ Aged, LD

↔ CPBS

0.8 ± 0.3

↔ Aged

↑ CPBS

↓ Cirr

1.6 ± 0.2

↑ Aged, LD, CPBS

—

100-200 ng/mL^b

310-340 ng/mL^c

^aMetabolically cleared by CYP3A. ^bProvides adequate anesthesia for superficial surgery. ^cProvides adequate anesthesia for abdominal surgery.

Reference: Bodenham A, et al. Alfentanil infusions in patients requiring intensive care. Clin Pharmacokinet, 1988, 75:216–226.

Alfuzosin^a

50%^b

↓ Food^c

11^d

∼90

6.4 ± 1.8^e

↔ RD^f

↓ LD^g

3.2 ± 1.1

6.3 ± 0.9^h

9ⁱ

16.6 ± 5.5 ng/mLⁱ

^aAlfuzosin is cleared primarily through CYP3A-dependent hepatic metabolism. Administered as racemate. ^bValue reported for 10-mg, extended-release formulation, once daily, given with a high-fat meal. ^cOral bioavailability in the fasted state is one-half that of the fed state. ^dValue reported in product label; however, route of administration uncertain. ^eR/S AUC ratio = 1.35. ^fStudy in patients with mild, moderate, or severe renal impairment; systemic exposure increased ∼50% and was independent of disease severity. ^gStudy in patients with moderate to severe liver impairment; CL/F reduced to one-third to one-quarter of control. ^hApparent t_1/2 = 9 hours for extended-release product; reflects absorption-limited kinetics. ⁱFollowing a 10-mg dose of extended-release formulation given once a day for 5 days.

References: McKeage K, et al. Alfuzosin: A review of the therapeutic use of the prolonged-release formulation given once daily in the management of benign prostatic hyperplasia. Drugs, 2002, 62:135–167. Drugs@FDA. Uroxatral NDA and label. NDA approved on 6/12/03; label approved on 5/20/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-287_Uroxatral_BioPharmr_P1.pdf and http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021287s013lbl.pdf. Accessed May 17, 2010.

Aliskiren^a

2.6^b

↓ Food^b

7.5

49 (47-51)

2.1

↓ RD^c

↔ LD^d

1.9

24-40^e

2.5^f

72 ± 67 ng/mL^f

^aAliskiren is cleared by both renal excretion and CYP3A-dependent hepatic metabolism; however, the relative contribution of each pathway to total drug clearance is unclear. ^bAbsolute bioavailability of 75 mg in hard gelatin capsule reported. Oral AUC decreased 71% with high-fat meal. ^cStudy in patients with mild to severe renal impairment; systemic exposure increased 1.0- to 2.5-fold but was independent of disease severity. ^dStudy in patients with mild to severe liver disease. ^et_1/2 estimated from single oral dose data. ^fFollowing 150 mg once daily to steady state in healthy adults.

References: Azizi M. Direct renin inhibition: Clinical pharmacology. J Mol Med, 2008,86:647–654. Azizi M, et al. Renin inhibition with aliskiren: Where are we now, and whereare we going? J Hypertens, 2006, 24:243–256. Vaidyanathan S, et al. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet, 2008, 27:515–531.

Allopurinol^a

53 ± 13

—

9.9 ± 2.4^b

↑RD, Aged^b

0.87 ± 0.13

A: 1.2 ± 0.3

O: 24 ± 4.5

A: 1.7 ± 1.0^c

O: 4.1 ± 1.4^c

A: 1.4 ± 0.5 μg/mL^c

O: 6.4 ± 0.8 μg/mL^c

^aData from healthy male and female subjects. Allopurinol (A) is rapidly metabolized to the pharmacologically active oxypurinol (O). ^blncreased oxypurinol AUC during renal impairment and in the elderly. ^cFollowing a single 300-mg oral dose.

References: PDR54, 2000, p. 1976. Tumheim K, et al. Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects. Br J Clin Pharmacol, 1999, 48:501–509.

Alosetron^a

57 (33-97)^b

—

8.3 (6.5-10.8)

↔ RD^c

↓ LD^d

0.91 (0.70-1.12)

1.4 (1.3-1.6)

1^e

5.5 (4.8-6.4) ng/mL^e

^aAlosetron is cleared primarily by CYP1A2-dependent hepatic metabolism. ^bAbsolute bioavailability of a 4-mg dose, as compared to IV infusion. ^cStudy in patients with CL_cr = 4-56 mL/min. ^dStudy in patients with moderate to severe liver impairment; oral AUC 1.6- to 14-fold higher than control. ^eFollowing a 1-mg oral dose, given twice a day to steady state.

References: Balfour JA, et al. Alosetron. Drugs, 2000, 59:511–518. Drugs@FDA. Lotronex NDA and label. NDA approved on 2/11/00; label approved on 4/1/08. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21107a_Lotronex_clinphrmr_P3.pdf and http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021107s013lbl.pdf. Accessed May 17, 2010. Koch KM, et al. Sex and age differences in the pharmacokinetics of alosetron. Br J Clin Pharmacol, 2002, 53:238–242.

Alprazolam

88 ± 16

71 ± 3

↑ LD

↔ Obes, Aged

0.74 ± 0.14^a

↓ Obes, LD, Aged^b

↔ RD

0.72 ± 0.12

↔ Obes, LD, Aged

12 ± 2

↑ Obes, LD, Aged^b

↔ RD

1.5 (0.5-3.0)^c

21 (15-32) ng/mL^c

^aMetabolically cleared by CYP3A and other cytochrome P450 isozymes. ^bData from male subjects only. ^cMean (range) from 19 studies following a single 1-g oral dose given to adults.

Reference: Greenblatt DJ, et al. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet, 1993, 24:453–471.

Ambrisentan^a

—^b

—

—^c

↔ RD

—

9^d

2-3^e

1200 ng/mL^e

^aAmbrisentan appears to be cleared primarily by the liver; however, the relative contribution from metabolism (glucuronidation and oxidation) versus biliary excretion is unclear. It is exported into the canalicular space of sandwich-cultured hepatocytes, possibly by P-glycoprotein. There also is evidence to suggest that it undergoes active hepatic uptake by organic anion transporting polypeptide (OATP) transporters. ^bThe absolute bioavailability is unknown. ^cNo IV dose data available; CL/F = 0.27 mL/min/kg following an oral dose in patients with pulmonary arterial hypertension (PAH). ^dEffective t_1/2 for accumulation of drug with multiple dosing in patients with PAH. A longer terminal t_1/2 = 14 hours also reported. ^eFollowing a 10-mg oral dose, given once a day to steady state in patients with PAH.

References: Croxtall JD, et al. Ambrisentan. Drugs, 2008, 68:2195–2204. Drugs@FDA. Letairis NDA and label. NDA approved on 5/15/07; label approved on 8/5/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022081s010lbl.pdf.

Amikacin

—

4 ± 8^a

1.3 ± 0.6

CL = 0.6CL_cr + 0.14

↓ Obes

↑ CP

0.27 ± 0.06

↔ Aged, Child, CF

↓ Obes

↑ Neo

2.3 ± 0.4

↑ RD

↔ Obes

↓ Burn, Child, CF

—

26 ± 4 μg/mL^b

^aAt a serum concentration of 15 μg/mL. ^bFollowing a 1-hour IV infusion of a 6.3 ± 1.4-mg/kg dose given three times a day to steady state in patients without renal impairment.

Reference: Bauer LA, et al. Influence of age on amikacin pharmacokinetics in patients without renal disease. Comparison with gentamicin and tobramycin. Eur J Clin Pharmacol, 1983, 24:639–642.

Amiodarone^a

46 ± 22

99.98 ± 0.01

1.9 ± 0.4^b

↔ Aged, Fem, CHF, RD

66 ± 44

25 ± 12 days^c

↔ Aged, Fem, RD

2-10^d

1.5-2.4 μg/mL^d

^aSignificant plasma concentrations of an active desethyl metabolite are observed (ratio of drug/metabolite ∼l); t_1/2 for metabolite = 61 days. ^bMetabolized by CYP3A. ^cLonger t_1/2 noted in patients (53 ± 24 days); all reported t_1/2s may be underestimated because of insufficient length of sampling. ^dFollowing a 400-mg/day oral dose to steady state in adult patients.

Reference: Gill J, et al. Amiodarone. An overview of its pharmacological properties, and review of its therapeutic use in cardiac arrhythmias. Drugs, 1992, 43:69–110.

Amlodipine^a

74 ± 17

↔ Aged

93 ± 1

↔ Aged

5.9 ± 1.5

↔ RD

↓ Aged, Hep

16 ± 4

↔ Aged

39 ± 8

↔ RD

↑ Aged, Hep

5.4-8.0^b

18.1 ± 7.1 ng/mL^b

↑ Aged

^aRacemic mixture; in young, healthy subjects, there are no apparent differences between the kinetics of the more active R-enantiomer and S-enantiomer. ^bFollowing a 10-mg oral dose given once daily for 14 days to healthy male adults.

Reference: Meredith PA, et al. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet, 1992, 22:22–31.

Amoxicillin

93 ± 10^a

86 ± 8

2.6 ± 0.4

↔ Child

↓ RD, Aged^b

0.21 ± 0.03

↔ RD, Aged

1.7 ± 0.3

↔ Child

↑ RD, Aged^b

1-2

IV: 46 ± 12 μg/mL^c

PO: 5 μg/mL^c

^aDose dependent; value shown is for a 375-mg dose; decreases to ∼50% at 3000 mg. ^bNo change if renal function is not decreased. ^cFollowing a single 500-mg IV bolus dose in healthy elderly adults or a single 500-mg oral dose in adults.

References: Hoffler D. The pharmacokinetics of amoxicillin [in German]. Adv Clin Pharmacol, 1974, 7:28–30. Sjovall J, et al. Intra- and inter-individual variation in pharmacokinetics of intravenously infused amoxicillin and ampicillin to elderly volunteers. Br J Clin Pharmacol, 1986, 27:171–181.

Amphotericin B^a

2-5

>90

0.46 ± 0.20^b

↔ RD, Prem

0.76 ± 0.52^c

18 ± 7^d

—

1.2 ± 0.33 μg/mL^e

^aData for amphotericin B shown. ^bData for eight children (ages 8 months to 14 years) yielded a linear regression, with CL decreasing with age: CL = −0.046 middot; age (years) + 0.86. Newborns show highly variable CL values. ^cVolume of central compartment. V_ss increases with dose from 3.4 L/kg for a 0.25-mg/kg dose to 8.9 L/kg for a 1.5-mg/kg dose. Also available as liposomal encapsulated formulations (ABELCET and AMBISOME). Amphotericin distribution and CL properties of these products are different from the nonencapsulated form; they have a terminal t_1/2 of 173 ± 78 and 110-153 hours, respectively; however, an effective steady-state concentration can be achieved within 4 days. ^dt_1/2 for multiple dosing. In single-dose studies, a prolonged dose-dependent t_1/2 is seen. ^eFollowing a 0.5-mg/kg IV dose of amphotericin B given as a 1-hour infusion, once daily for 3 days. Whole blood concentrations (free and liposome encapsulated) of 1.7 ± 0.8 μg/mL and 83 ± 35 μg/mL were reported following a 5-mg/kg/day IV dose(presumed 60- to 120-minute infusion) of ABELCET and AMBISOME, respectively.

References: Gallis HA, et al. Amphotericin B: 30 years of clinical experience. Rev Infect Dis, 1990, 12:308–329. PDR54, 2000, pp. 1090–1091, 1654.

Anastrozole^a

<10

∼40

—

↓ LD^b

—

≤2^c

46 ng/mL^c

^aData from healthy pre- and postmenopausal female subjects. Metabolized by CYPs and UGTs. ^bCL/F reduced, stable alcoholic cirrhosis. ^cC_max and T_max following a single 3-mg oral dose. Accumulates 3- to 4-fold from single to multiple daily dosing.

References: L⊘nning PE, et al. Pharmacological and clinical profile of anastrozole. Breast Cancer Res Treat, 1998, 49(suppl):S53–S57; discussion S73–S77. PDR54, 2000, p. 537. Plourde PV, et al. ARIMIDEX: A new oral, once-a-day aromatase inhibitor. J Steroid Biochem Mol Biol, 1995, 53:175–179.

Aprepitant^a

60-65^b

Negligible

>95

0.89-1.29^b

1.0

9-13

4^c

1.6 μg/mL^c

^aExtensively metabolized, primarily by CYP3A4. No significant gender differences. ^bExhibits a slightly disproportional increase in AUC with increasing oral dose. ^cFollowing a single 125-mg oral dose.

References: PDR58, 2004, pp. 1980–1981. Sanchez RI, et al. Cytochrome P4503A4 is the major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos, 2004, 32:1287–1292.

Aripiprazole^a

>99

0.83 ± 0.17^b

4.9^b

47 ± 10

3.0 ± 0.6^c

242 ± 36 ng/mL^c

^aEliminated primarily by CYP2D6- and CYP3A4-dependent metabolism. The major metabolite, dehydro-aripiprazole, has affinity for D₂ receptors similar to parent drug; found at 40% of parent drug concentration in plasma; t_1/2 is 94 hours. CYP2D6 poor metabolizers exhibit increased exposure (80%) to parent drug but reduced exposure (30%) to the active metabolite. No significant gender differences. ^bCL/F and V/F at steady state reported. ^cFollowing a 15-mg oral dose given once daily for 14 days.

References: DeLeon A, et al. Aripiprazole: A comprehensive review of its pharmacology, clinical efficacy, and tolerability. Clin Ther, 2004, 26:649–666. Mallikaarjun S, et al. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol, 2004, 44:179–187. PDR58, 2004, pp. 1034–1035.

Atazanavir^a

—^b

↑ Food

3.4 ± 1.0^c

↓ LD

1.6-2.7^c

7.9 ± 2.9

↑ LD

2.5^d

5.4 ± 1.4 μg/mL^d

^aUndergoes extensive hepatic metabolism, primarily by CYP3A. Pharmacokinetic data reported for healthy adults. No significant gender or age differences. ^bAbsolute bioavailability is not known, but food enhances the extent of absorption. ^cCL/F and V/F reported. Metabolic elimination affected by inhibitors and inducers of CYP3A. Co-administration with low-dose ritonavir increases systemic atazanavir exposure. ^dFollowing a 400-mg oral dose given with a light meal once daily to steady state.

References: Orrick JJ, et al. Atazanavir. Ann Pharmacother, 2004, 38:1664–1674. PDR58, 2004, p. 1081.

Atenolol^a

58 ± 16

94 ± 8

2.4 ± 0.3

↓ Aged

1.3 ± 0.5^b

6.1 ± 2.0^c

↑ RD, Aged

3.3 ± 1.3^d

0.28 ± 0.09 μg/mL^d

^aAtenolol is administered as a racemic mixture. No significant differences in the pharmacokinetics of the enantiomers. ^bV_area reported. ^ct_1/2 of R- and S-atenolol are similar. ^dFollowing a single 50-mg oral dose.

References: Boyd RA, et al. The pharmacokinetics of the enantiomers of atenolol. Clin Pharmacol Ther, 1989, 45:403–410. Mason WD, et al. Kinetics and absolute bioavailability of atenolol. Clin Pharmacol Ther, 1979, 25:408–415.

Atomoxetine^a

EM: 63^b

PM: 94^b

1-2%

98.7 ± 0.3

EM: 6.2^b

PM: 0.60^b

EM: ↓ LD

EM: 2.3^b

PM: 1.1^b

EM: 5.3^b

PM: 20^b

EM/PM: 2^c

EM: 160 ng/mL^c

PM: 915 ng/mL^c

^aMetabolized by CYP2D6 (polymorphic). Poor metabolizers (PM) exhibit a higher oral bioavailability, higher C_max, lower CL, and longer t_1/2 than extensive metabolizers (EM). No differences between adults and children >6 years of age. ^bCL/F, V/F, and t_1/2 measured at steady state. ^cFollowing a 20-mg oral dose given twice daily for 5 days.

References: Sauer JM, et al. Disposition and metabolic fate of atomoxetine hydrochloride: The role of CYP2D6 in human disposition and metabolism. Drug Metab Dispos, 2003, 37:98–107. Simpson D, et al. Atomoxetine: A review of its use in adults with attention deficit hyperactivity disorder. Drugs, 2004, 64:205–222.

Atorvastatin^a

≥98

29^b

↓ LD,^c Aged

↔ RD

∼5.4^b

19.5 ± 9.6

↑ LD,^b Aged

2.3 ± 0.96^d

14.9 ± 1.8 ngEq/mL^d

^aData from healthy adult male and female subjects. No clinically significant gender differences. Atorvastatin undergoes extensive CYP3A-dependent first-pass metabolism. Metabolites are active and exhibit a longer t_1/2 (20-30 hours) than parent drug. ^bMean CL/F parameter calculated from reported AUC data at steady state after a once-a-day 20-mg oral dose, assuming a 70-kg body weight. ^cAUC following oral administration increased, mild to moderate hepatic impairment. ^dFollowing a 20-mg oral dose once daily for 14 days.

References: Gibson DM, et al. Effect of age and gender on pharmacokinetics of atorvastatin in humans. J Clin Pharmacol, 1996, 36:242–246. Lea AP, et al. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs, 1997, 53:828–847. PDR54, 2000, p. 2254.

Azathioprine^a

60 ± 31^b

—

57 ± 31^c

0.81 ± 0.65^c

0.16 ± 0.07^c

↔ RD

MP: l-2^d

MP: 20-90 ng/mL^d

^aAzathioprine is metabolized to mercaptopurine (MP), listed later in this table. ^bDetermined as the bioavailability of MP; intact azathioprine is undetectable after oral administration because of extensive first-pass metabolism. Kinetic values are for IV azathioprine. ^cData from kidney transplant patients. ^dMP concentration following a 135 ± 34-mg oral dose of azathioprine given daily to steady state in kidney transplant patients.

Reference: Lin SN, et al. Quantitation of plasma azathioprine and 6-mercaptopurine levels in renal transplant patients. Transplantation, 1980, 29:290–294.

Azithromycin

34 ± 19

↓ Food (capsules)

↑ Food (suspension)

7-50^a

40^b

↔ LD

2-3^c

0.4 μg/mL^c

^aDose-dependent plasma binding. The bound fraction is 50% at 50 ng/mL and 12% at 500 ng/mL. ^bA longer terminal plasma t_1/2 of 68 ± 8 hours, reflecting release from tissue stores, overestimates the multiple-dosing t_1/2. ^cFollowing a 250-mg/day oral dose to adult patients with an infection.

Reference: Lalak NJ, et al. Azithromycin clinical pharmacokinetics. Clin Pharmacokinet, 1993, 25:370–374.

Baclofen^a

>70^b

69 ± 14

31 ± 11

2.72 ± 0.93^c

↓ RD^d

0.81 ± 0.12^c

3.75 ± 0.96

1.0 (0.5-4)^e

160 ± 49 ng/mL^e

^aData from healthy adult male subjects. ^bBioavailability estimate based on urine recovery of unchanged drug after oral dose. ^cCL/F, V_area/F reported for intestinal infusion of drug. ^dLimited data suggest CL/F reduced with renal impairment. ^eFollowing a single 10-mg oral dose.

References: Kochak GM, et al. The pharmacokinetics of baclofen derived from intestinal infusion. Clin Pharmacol Ther, 1985, 38:251–257. Wuis EW, et al. Plasma and urinary excretion kinetics of oral baclofen in healthy subjects. Eur J Clin Pharmacol, 1989, 37:181–184.

Bicalutamide^a

—

1.7 ± 0.3

R: 0.043 ± 0.013^b

S: 7.3 ± 4.0^b

↔ LD, RD, Aged

—

R: 139 ± 32

S: 29 ± 8.6

↑ LD^c

R: 23.4^d

S: 20.7^d

SD, R: 734 ng/mL^d

SD, S: 84 ng/mL^d

MD, R/S: 8.9 ± 3.5 μg/mL

^aData from healthy male subjects. Exhibits stereoselective metabolism—S-enantiomer, primarily glucuronidation; R-enantiomer, primarily oxidation. ^bCL/F reported for oral dose. ^cIncreased t_1/2 of R-enantiomer, severe LD. ^dFollowing a 50-mg tablet administered as a single dose (SD) or a multiple dose (MD), once a day to steady state.

References: Cockshott ID, et al. The effect of food on the pharmacokinetics of the bicalutamide ("Casodex") enantiomers. Biopharm Drug Dispos, 1997, 18:499–507. McKillop D, et al. Metabolism and enantioselective pharmacokinetics of Casodex in man. Xenobiotica, 1993, 23:1241–1253. PDR54, 2000, p. 538.

Buprenorphine^a

IM: 40 to >90

SL: 51 ± 30

BC: 28 ± 9

Negligible

13.3 ± 0.59

↑ Child^b

1.44 ± 0.11

↑ Child^b

2.33 ± 0.24

↓ Child^b

IM: 0.08^c

SL:0.7 ± 0.1^c

BC: 0.8 ± 0.2^c

IM: 3.6 ± 3.0 ng/mL^c

SL: 3.3 ± 0.8 ng/mL^c

BC: 2.0 ± 0.6 ng/mL^c

^aData from male and female subjects undergoing surgery. Buprenorphine is metabolized in the liver by both oxidative (N-dealkylation) and conjugative pathways. ^bCL, 60 ± 19 mL/min/kg; V_ss, 3.2 L/kg; t_1/2, 1.03 ± 0.22 hour; children 4-7 years of age. ^cFollowing a 0.3-mg IM, 4-mg sublingual (SL), 4-mg buccal (BC) dose.

References: Bullingham RE, et al. Buprenorphine kinetics. Clin Pharmacol Ther, 1980, 28:667–672. Cone EJ, et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos, 1984, 12:577–581. Kuhlman JJ, et al. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol, 1996, 20:369–378. Olkkola KT, et al. Pharmacokinetics of intravenous buprenorphine in children. Br J Clin Pharmacol, 1989, 28:202–204.

Bupropion^a

—

>80%

36.0 ± 2.2^b

↓ Aged, LD^c

↔ Alcohol

18.6 ± 1.2^b

↔ Alcohol

11 ± 1^b

(7.9-18.4)

↑ Aged, LD^c

↔ Alcohol

IR: 1.6 ± 0.1^d

SR: 3.1 ± 0.3^d

IR: 141 ± 19 ng/mL^d

SR: 142 ± 28 ng/mL^d

^aData from healthy adult male volunteers. Bupropion appears to undergo extensive first-pass metabolism by CYP2B6 and other CYP isozymes. Some metabolites accumulate in blood and are active. ^bCL/F, V_ss/F, and t_1/2 reported for oral dose. Range of mean terminal t_1/2 from four different studies shown in parentheses. ^cCL/F reduced, alcoholic liver disease. ^dFollowing a single100-mg immediate-release (IR) or 150-mg sustained-release (SR) dose.

References: DeVane CL, et al. Disposition of bupropion in healthy volunteers and subjects with alcoholic liver disease. J Clin Psychopharmacol, 1990, 10:328–332. Hsyu PH, et al. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers.J Clin Pharmacol, 1997, 37:737–743. PDR54, 2000, p. 1301. Posner J, et al. Alcohol and bupropion pharmacokinetics in healthy male volunteers. Eur J Clin Pharmacol, 1984, 26:627–630. Posner J, et al. The disposition of bupropion and its metabolites in healthy male volunteers after single and multiple doses. Eur J Clin Pharmacol, 1985, 29:97–103.

Buspirone^a

3.9 ± 4.3

↑ Food^b

<0.1

>95

28.3 ± 10.3

↓ LD,^c RD^d

5.3 ± 2.6

2.4 ± 1.1

↑ LD, RD

0.71 ± 0.06^e

1.66 ± 0.21 ng/mL^e

^aData from healthy adult male subjects. No significant gender differences. Undergoes extensive CYP3A-dependent first-pass metabolism. The major metabolite (l-pyrimidinyl piperazine) is active in some behavioral tests in animals (one-fifth potency) and accumulates in blood to levels severalfold higher than buspirone. ^bBioavailability increased ∼84%; appears to be secondary to reduced first-pass metabolism. ^cCL/F reduced, hepatic cirrhosis. ^dCL/F reduced, mild renal impairment; unrelated to CL_cr. ^eFollowing a single 20-mg oral dose.

References: Barbhaiya RH, et al. Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses. Eur J Clin Pharmacol, 1994, 46:41–47. Gammans RE, et al. Metabolism and disposition of buspirone. Am J Med, 1986, 80:41–51.

Busulfan

70 (44-94)

2.7-14

4.5 ± 0.9^a

0.99 ± 0.23^a

2.6 ± 0.5

2.6 ± 1.5

Low: 65 ± 27 ng/mL^b

High: 949 ± 278 ng/mL^b

^aCL/F and V_area/F reported. ^bFollowing a single 4-mg oral dose (low) given to patients with chronic myelocytic leukemia or a single 1-mg/kg oral dose (high) given as ablative therapy to patients undergoing bone marrow transplantation.

References: Ehrsson H, et al. Busulfan kinetics. Clin Pharmacol Ther, 1983, 34:86–89. Schuler US, et al. Pharmacokinetics of intravenous busulfan and evaluation of the bioavailability of the oral formulation in conditioning for haematopoietic stem cell transplantation. Bone Marrow Transplant, 1998, 22:241–244.

Calcitriol^a

PO: ∼61

IP: ∼67

<10%

99.9

0.43 ± 0.04

—

16.5 ± 3.1^b

↑ Child^c

PO: 3-6^d

IP: 2-3^d

IV: ∼460 pg/mL^d

PO: ∼90 pg/mL^d

IP: ∼105 pg/mL^d

^aData from young (15-22 years) patients on peritoneal dialysis. Metabolized by 23-, 24-, and 26-hydroxylases and also excreted into bile as its glucuronide. ^bCalcitriol t_1/2 is 5-8 hours in healthy adult subjects. ^cOral dose t_1/2 = 27 ± 12 hours, children 2-16 years. ^dFollowing a single 60-ng/kg IV, intraperitoneal (IP) dialysate, or PO dose. Baseline plasma levels were <10 pg/mL.

References: Jones CL, et al. Comparisons between oral and intraperitoneal 1,25-dihydroxyvitamin D₃ therapy in children treated with peritoneal dialysis. Clin Nephrol, 1994, 42:44–49. PDR54, 2000, p. 2650. Salusky IE, et al. Pharmacokinetics of calcitriol in continuous ambulatory and cycling peritoneal dialysis patients. Am J Kidney Dis, 1990, 16:126–132.

Taylor CA, et al. Clinical pharmacokinetics during continuous ambulatory peritoneal dialysis. Clin Pharmacokinet, 1996, 31:293–308.

Capecitabine^a

—

↓ Food^b

<60

145 (34%) L/hr/m^{2 c,d}

↓ LD^e

270 L/m^{2 c,d}

C: 1.3 (146%)^c

5-FU: 0.72 (16%)^c

C: 0.5 (0.5-1)^f

5-FU: 0.5 (0.5-2.1)^f

↓ Food

C: 6.6 ± 6.0 μg/mL^f

5-FU: 0.47 ± 0.47 μg/mL^f

^aData from male and female patients with cancer. Capecitabine (C) is a prodrug for 5-fluorouracil (5-FU; active), listed later in this table. It is well absorbed, and bioactivation is sequential in liver and tumor. ^bAUC for C and 5-FU decreased. ^cGeometric mean (coefficient of variation). ^dCL/F and V_area/F reported for oral dose. ^eCL/F reduced but no change in 5-FU AUC, liver metastasis. ^fFollowing 1255 mg/m².

References: Dooley M, et al. Capecitabine. Drugs, 1999, 58:69–76; discussion 77–78.

Reigner B, et al. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res, 1998, 4:941–948.

Carbamazepine^a

>70

74 ± 3

↔ RD, LD, Preg

1.3 ± 0.5^b,c

↑ Preg

↔ Child, Aged, Smk

1.4 ± 0.4^b

↔ Child, Neo, Aged

15 ± 5^b,c

↔ Child, Neo, Aged

4-8^d

9.3 (2-18) μg/mL^d

^aA metabolite, carbamazepine-10,11-epoxide, is equipotent in animal studies. Its formation is catalyzed primarily by CYP3A and secondarily by CYP2C8. ^bData from oral, multiple-dose regimen; values are CL/F and V_area/F. ^cData from multiple-dose regimen. Carbamazepine induces its own metabolism; for a single dose, CL/F = 0.36 ± 0.07 mL/min/kg and t_1/2 = 36 ± 5 hours. CL also increases with dose. ^dMean (range) steady-state concentration following a daily 18.4-mg/kg oral dose (immediate release) given to adult patients with epilepsy. Therapeutic range for control of psychomotor seizures is 4-10 μg/mL.

References: Bertilsson L, et al. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update. Clin Pharmacokinet, 1986, 11:177–198. Troupin A, et al. Carbamazepine—A double-blind comparison with phenytoin. Neurology, 1977, 27:511–519.

Carbidopa^a

—^b

5.3 ± 2.1

—

18 ± 7^c

—

∼2

2.1 ± 1.0

S: 165 ± 77 ng/mL^d

S-CR: 81 ± 28 ng/mL^d

^aData from healthy adult subjects. Combined with levodopa for treatment of Parkinson's disease. ^bAbsolute bioavailability is unknown, but it is presumably low based on a high value for CL/F. Bioavailability of sinemet cr (S-CR) is 55% of standard sinemet (S). ^cCL/F reported for 2 tablets of sinemet 25/100. ^dFollowing a single oral dose of 2 tablets sinemet 25/100 or1 tablet sinemet CR 50/200.

Reference: Yeh KC, et al. Pharmacokinetics and bioavailability of Sinemet CR: A summary of human studies. Neurology, 1989, 39:25–38.

Carboplatin^a

—

77 ± 5

1.5 ± 0.3

↓ RD

0.24 ± 0.03

2 ± 0.2

↑ RD

0.5^b

39 ± 17 μg/mL^b

^aMeasure of ultrafilterable platinum, which essentially is unchanged carboplatin. ^bFollowing a single 170 to 500-mg/m² IV dose (30-minute infusion) given to adult patients with ovarian cancer.

Reference: Gaver RC, et al. The disposition of carboplatin in ovarian cancer patients. Cancer Chemother Pharmacol, 1988, 22:263–270.

Carvedilol^a

S-(−): 15

R-(+): 31

↑ Cirr

95^b

8.7 ± 1.7

↓ LD

↔ RD, Aged

1.5 ± 0.3

↑ Cirr

2.2 ± 0.3^c

↑, ↔ LD

↔ RD, Aged

1.3 ± 0.3^d

105 ± 12 ng/mL^d

^aRacemic mixture: S-(−)-enantiomer responsible for β₁ adrenergic–receptor blockade. R-(+)- and S-(−)-enantiomers have nearly equivalent α₁-receptor blocking activity. ^bR-(+)-enantiomer is more tightly bound than the S-(−)-antipode. ^cLonger t_1/2 of ∼6 hours has been measured at lower concentrations. ^dFollowing a 12.5-mg oral dose given twice a day for 2 weeks to healthy young adults.

References: Morgan T. Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin Pharmacokinet, 1994, 26:335–346. Morgan T, et al. Pharmacokinetics of carvedilol in older and younger patients. J Hum Hypertens, 1990, 4:709–715.

Cefazolin

>90

80 ± 16

89 ± 2

↓ RD, LD, CPBS, Neo, Child

0.95 ± 0.17

↓ RD, CPBS

↑ Preg

↔ Neo, Obes, Child, LD

0.19 ± 0.06^a

↑ RD, Neo

↔ Preg, Obes, Child, LD

2.2 ± 0.02

↑ RD, Neo, CPBS

↓ Preg, LD

↔ Obes, Child

IM: 1.7 ± 0.7^b

IV: 237 ± 285 μg/mL^b

IM: 42 ± 9.5 μg/mL^b

^aV_area reported. ^bFollowing a single 1-g IV (model-fitted C_max) or IM dose to healthy adults.

Reference: Scheld WM, et al. Moxalactam and cefazolin: Comparative pharmacokinetics in normal subjects. Antimicrob Agents Chemother, 1981, 79:613–619.

Cefdinir

Cap: 16-21^a

Susp: 25^a

↓ Iron

13-23^b

89^c

↓ RD

11-15^d

1.6-2.1^d

1.4-1.5

Cap: 3 ± 0.7^e

Susp: 2 ± 0.4^e

Cap: 2.9 ± 1.0 μg/mL^e

Susp: 3.9 ± 0.6 μg/mL^e

^aBioavailability following ingestion of a capsule (Cap) or suspension (Susp) formulated dose. ^bDetermined after a single oral dose. ^cLower plasma protein binding (71-74%) reported in patients undergoing dialysis. ^dCL/F and V/F reported. ^eFollowing ingestion of a single 600-mg capsule given to adults or a 14-mg/kg suspension dose given to children (6 months to 12 years). No accumulation after multiple dosing.

References: Guay DR. Pharmacodynamics and pharmacokinetics of cefdinir, an oral extended spectrum cephalosporin. Pediatr Infect Dis J, 2000, 19:S141–S146. PDR58, 2004, p. 503. Tomino Y, et al. Pharmacokinetics of cefdinir and its transfer to dialysate in patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis. Arzneimittelforschung, 1998, 48:862–867.

Cefepime^a

—

16-19

1.8 (1.7-2.5)^b

↓ RD^c

0.26 (0.24-0.31)^d

2.1 (1.3-2.4)^b

↑ RD^c

—

65 ± 7 μg/mL^e

^aData from healthy adult patients. Available only in parenteral form. ^bMedian (range) of reported CL and t_1/2 values from 16 single-dose studies. ^cMild renal impairment. ^dMedian (range) of reported V_ss from 6 single-dose studies. ^eFollowing a 1-g IV dose.

References: Okamoto MP, et al. Cefepime clinical pharmacokinetics. Clin Pharmacokinet, 1993, 25:88–102. Rybak M. The pharmacokinetic profile of a new generation of parenteral cephalosporin. Am J Med, 1996, 100:39S–44S.

Ceftazidime

—

IM: 91

84 ± 4

↔ CF

21 ± 6

CL = 1.05CL_cr + 0.12

↔ CF, Burn

0.23 ± 0.02

↔ RD, CF

↑ Aged, Burn

1.6 ± 0.1

↑ RD, Prem, Neo, Aged

↔ CF

IM: 0.7-1.3^a

IV: 119-146 μg/mL^a

IM: 29-39 μg/mL^a

^aRange of mean data from different studies following a 1-g bolus IV or IM dose given to healthy adults.

Reference: Balant L, et al. Clinical pharmacokinetics of the third generation cephalosporins. Clin Pharmacokinet, 1985, 10:101–143.

Ceftriaxone^a

IM: ∼100%

43 ± 10^b

96% (0.5 μg/mL) to 83% (300 μg/mL)^c

↓ LD^d

0.5 g: 0.22 ± 0.04

2 g: 0.28 ± 0.04^e

↓ RD^f

↓ LD^d

0.5 g: 0.12 ± 0.02

2 g: 0.14 ± 0.01^e

5.9-6.5^e

↑ RD^f

↔ LD^g

IM: 2

IV^h

0.5 g: 101 ± 13 μg/mL

2.0 g: 280 ± 39 μg/mL

IM^h

0.5 g: 65 μg/mL

1.0 g: 114 μg/mL

^aCeftriaxone is most commonly administered by IV or IM injection and cleared unchanged by both renal and biliary excretion. ^bValue for a 2-g IV dose; similar values reported for 0.5- and 1-g doses. ^cExhibits saturable binding. ^dStudy in patients with mild to severe hepatic impairment. ^eTotal clearance and distribution volume vary with dose and plasma free fraction; however, the unbound concentration at steady state is dose proportional. Mean t_1/2 values for 0.5- to 2-g doses not significantly different. ^fStudy in anephric patients with normal nonrenal clearance. Much greater increases seen in patients with both renal and hepatic disease. ^gImpact of liver disease is limited by apparent offsetting changes in plasma-free fraction and unbound intrinsic clearance. ^hFollowing twice-daily dosing to steady state.

References: Patel IH, et al. Pharmacokinetics of ceftriaxone in humans. Antimicrob Agents Chemother, 1981, 20:634–641. Pollock AA, et al. Pharmacokinetic characteristics of intravenous ceftriaxone in normal adults. Antimicrob Agents Chemother, 1982, 22:816–823. Yuk JH, et al. Clinical pharmacokinetics of ceftriaxone. Clin Pharmacokinet, 1989, 17:223–235.

Celecoxib^a

—

↑ Food^b

∼97

6.60 ± 1.85^c

↓ Aged, LD^d

↑ RD^e

6.12 ± 2.08^c

11.2 ± 3.47

2.8 ± 1.0^f

↑ Food

705 ± 268 ng/mL^f

^aData from healthy subjects. Cleared primarily by CYP2C9 (polymorphic). ^bHigh-fat meal. Absolute bioavailability is unknown. ^cCL/F and V/F values reported. ^dCL/F reduced, mild or moderate hepatic impairment. ^eCL/F increased, moderate renal impairment, but unrelated to CL_cr. ^fFollowing a single 200-mg oral dose.

References: Goldenberg MM. Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis. Clin Ther, 1999, 21:1497–1513; discussion 1427–1428. PDR54, 2000, p. 2334.

Cephalexin

90 ± 9

91 ± 18

14 ± 3

4.3 ± 1.1^a

↓ RD

0.26 ± 0.03^a

↔ RD

0.90 ± 0.18

↑ RD

1.4 ± 0.8^a

28 ± 6.4 μg/mL^a

^aFollowing a single 500-mg oral dose given to healthy male adults.

Reference: Spyker DA, et al. Pharmacokinetics of cefaclor and cephalexin: Dosage nomograms for impaired renal function. Antimicrob Agents Chemother, 1978, 14:172–177.

Cetirizine^a

Rac: >70^b

Levo: >68^b

Rac: 70.9 ± 7.8

Levo: 68.1 ± 10.2

Rac: 89.2 ± 0.4

Levo: 92.0 ± 0.3

Rac: 0.74 ± 0.19^c

Levo: 0.62 ± 0.11^c

Rac: ↓ LD,^d RD,^e Aged

Levo: ↓ RD

Rac/Levo: ↑ Child^f

Rac: 0.58 ± 0.16^c

Levo: 0.41 ± 0.10

Rac: 9.42 ± 2.4

Levo: 7.8 ± 1.6

Rac: ↑ LD, RD, Aged

Levo: ↑ RD

Rac/Levo: ↓ Child

Rac: 0.9 ± 0.2^g

Levo: 0.8 ± 0.5^g

Rac: 313 ± 45 ng/mL^g

Levo: 270 ± 40 ng/mL^g

^aData from healthy male and female subjects receiving cetirizine (Rac) or the active R-enantiomer, levocetirizine (Levo). ^bBased on recovery of unchanged drug in urine. ^cCL/F, V_d/F reported for oral dose. ^dCL/F reduced, hepatocellular and cholestatic liver diseases. ^eCL/F reduced, moderate to severe renal impairment. ^fCL/F increased, ages 1-5 years. ^gFollowing a single 10-mg oral dose of Rac or 5 mg of Levo.

References: Baltes E, et al. Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers. Fundam Clin Pharmacol, 2001, 15:269–277. Benedetti MS, et al. Absorption, distribution, metabolism and excretion of [14C]levocetirizine, the R enantiomer of cetirizine, in healthy volunteers. Eur J Clin Pharmacol, 2001, 57:571–582. Horsmans Y, et al. Single-dose pharmacokinetics of cetirizine in patients with chronic liver disease. J Clin Pharmacol, 1993, 33:929–932. Matzke GR, et al. Pharmacokinetics of cetirizine in the elderly and patients with renal insufficiency. Ann Allergy, 1987, 59:25–30. PDR54, 2000, p. 2404. Spicák V, et al. Pharmacokinetics and pharmacodynamics of cetirizine in infants and toddlers. Clin Pharmacol Ther, 1997, 61:325–330. Strolin Benedetti M, et al. Stereoselective renal tubular secretion of levocetirizine and dextrocetirizine, the two enantiomers of the H1-antihistamine cetirizine. Fundam Clin Pharmacol, 2008, 22:19–23.

Chloroquine^a

∼80

52-58^b

S: 66.6 ± 3.3^c

R: 42.7 ± 2.1

↔ RD

3.7-13^b

132-261^b

10-24 days^b,d

IM: 0.25^e

PO: 3.6 ± 2.0^e

IV: 837 ± 248 ng/mL

IM: 57-480 ng/mL

PO: 76 ± 14 ng/mL

^aActive metabolite, desethylchloroquine, accounts for 20 ± 3% of urinary excretion; t_1/2 = 15 ± 6 days. Racemic mixture; kinetic parameters for the two isomers are slightly different [e.g., mean residence time = 16.2 days and 11.3 days for the R-isomer and S-isomer, respectively]. ^bRange of mean values from different studies (IV administration). ^cConcentrates in red blood cells. Blood-to-plasma concentration ratio for racemate = 9. ^dA longer t_1/2 (41 ± 14 days) has been reported with extended blood sampling. ^eFollowing a single 300-mg IV dose (24-minute infusion) of chloroquine HCl or a single 300-mg IM or oral dose of chloroquine phosphate given to healthy adults. Effective concentrations against Plasmodium vivax and Plasmodium falciparum are15 ng/mL and 30 ng/mL, respectively. Diplopia and dizziness can occur >250 ng/mL.

References: Krishna S, et al. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin Pharmacokinet, 1996, 30:263–299. White NJ. Clinical pharmacokinetics of antimalarial drugs. Clin Pharmacokinet, 1985, 10:187–215.

Chlorpheniramine^a

41 ± 16

0.3-26^b

70 ± 3

1.7 ± 0.1

↑ Child

3.2 ± 0.3

↔ Child

20 ± 5

↓ Child

IR: 2-3^c

SR: 5.7-8.1^c

IR: 16-71 ng/mL^c

SR: 17-76 ng/mL^c

^aAdministered as a racemic mixture; reported parameters are for racemic drug. Activity comes predominantly from S-(+)-enantiomer, which has a 60% longer t_1/2 than the R-(–)-enantiomer. ^bRenal elimination increases with increased urine flow and lower pH. ^cRange of data from different studies following a 4-mg oral immediate-release (IR) dose given every 4-6 hours to steady state or following an 8-mg oral sustained-release (SR) dose given every 12 hours to steady state, both in healthy adults.

Reference: Rumore MM. Clinical pharmacokinetics of chlorpheniramine. Drug Intell Clin Pharm, 1984, 18:701–707.

Chlorpromazine^a

32 ± 19^b

95-98

↔ RD

8.6 ± 2.9^c

↓ Child

↔ LD

21 ± 9^c

30 ± 7^c

1-4^d

25-150 ng/mL^d

^aActive metabolites, 7-hydroxychlorpromazine (t_1/2 = 25 ± 15 hours) and possibly chlorpromazine N-oxide, yield AUCs comparable to the parent drug (single doses). ^bAfter a single dose. Bioavailability may decrease to ∼20% with repeated dosing. ^cCL/F, V_area, and terminal t_1/2 following IM administration. ^dFollowing a 100-mg oral dose given twice a day for 33 days to adult patients. Neurotoxicity (tremors and convulsions) occurs at concentrations of 750-1000 ng/mL.

Reference: Dahl SG, et al. Pharmacokinetics of chlorpromazine after single and chronic dosage. Clin Pharmacol Ther, 1977, 21:437–448.

Chlorthalidone

64 ± 10

65 ± 9^a

75 ± 1

0.04 ± 0.01

↓ Aged

0.14 ± 0.07

47 ± 22^b

↑ Aged

13.8 ± 6.3^c

3.7 ± 0.9 μg/mL^c

^aValue is for 50- and 100-mg doses; renal CL is decreased at an oral dose of 200 mg, and there is a concomitant decrease in the percentage excreted unchanged. ^bChlorthalidone is sequestered in erythrocytes. t_1/2 is longer if blood, rather than plasma, is analyzed. Parameters reported based on blood concentrations. ^cFollowing a single 50-mg oral dose (tablet) given to healthy male adults.

Reference: Williams RL, et al. Relative bioavailability of chlorthalidone in humans: Adverse influence of polyethylene glycol. J Pharm Sci, 1982, 71:533–535.

Cidofovir^a

SC: 98 ± 10

PO: <5

70.1 ± 21.4^b

2.1 ± 0.6^b

↓ RD^c

0.36 ± 0.13^b

2.3 ± 0.5^b

↑ RD

—

19.6 ± 7.2 μg/mL^d

^aData from patients with HIV infection and positive for cytomegalovirus. Cidofovir is activated intracellularly by phosphokinases. For parenteral use. ^bParameters reported for a dose given in the presence of probenecid. ^cCL reduced, mild renal impairment (cleared by high-flux hemodialysis). ^dFollowing a single 5-mg/kg IV infusion given over 1 hour, with concomitant oral probenecid and active hydration.

References: Brody SR, et al. Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or high-flux hemodialysis. Clin Pharmacol Ther, 1999, 65:21–28. Cundy KC, et al. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother, 1995, 39:1247–1252. PDR54, 2000, p. 1136. Wachsman M, et al. Pharmacokinetics, safety and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus-infected subjects. Antiviral Res, 1996, 29:153–161.

Cinacalcet^a

∼20

↑ Food

—^b

93-97

∼18

↓ LD

∼17.6

34 ± 9

↑ LD

2-6

10.6 ± 2.8 ng/mL^c

^aCinacalcet is a chiral molecule; the R-enantiomer is more potent than the S-enantiomer and is thought to be responsible for the drug's pharmacological activity. Cinacalcet is metabolized primarily by CYP3A4, CYP2D6, and CYP1A2. ^bUnreported, but presumably negligible. ^cFollowing a single 75-mg oral dose.

References: Joy MS, et al. Calcimimetics and the treatment of primary and secondary hyperparathyroidism. Ann Pharmacother, 2004, 38:1871–1880. Kumar GN, et al. Metabolism and disposition of calcimimetic agent cinacalcet HCl in humans and animal models. Drug Metab Dispos, 2004, 32:1491–1500. Pharmacology and toxicology review of NDA. Application 21–688. U.S. FDA, CDER. Available at: http://www.fda.gov/drugs at fda_docs/nda/2004/21-688.pdf. Sensipar_Pharmr_Pl.pdf. Accessed July 7, 2010.

Ciprofloxacin

60 ± 12

50 ± 5

7.6 ± 0.8

↓ RD, Aged

↑ CF

2.2 ± 0.4^a

↓ Aged

↔ CF

3.3 ± 0.4

↑ RD

↔ Aged

↓ CF

0.6 ± 0.2^b

2.5 ± 1.1 μg/mL^b

^aV_area reported. ^bFollowing a 500-mg oral dose given twice daily for ≥3 days to patients with chronic bronchitis or bronchiectasis.

References: Begg EJ, et al. The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing. Br J Clin Pharmacol, 2000, 49:32–38. Sorgel F, et al. Pharmacokinetic disposition of quinolones in human body fluids and tissues. Clin Pharmacokinet, 1989, 16(suppl):5–24.

Cisplatin^a

—

23 ± 9

—^b

6.3 ± 1.2

0.28 ± 0.07

0.53 ± 0.10

—

2 Hr: 3.4 ± 1.1 μg/mL^c

7 Hr: 1.0 ± 0.4 μg/mL^c

^aEarly studies measured total platinum, rather than the parent compound; values reported here are for parent drug in seven patients with ovarian cancer (mean CL_cr = 66 ± 27 mL/min). ^bPlatinum will form a tight complex with plasma proteins (90%). ^cFollowing a single100-mg/m² IV dose given as an ∼2- or 7-hour infusion to ovarian cancer patients.

Reference: Reece PA, et al. Disposition of unchanged cisplatin in patients with ovarian cancer. Clin Pharmacol Ther, 1987, 42:320–325.

Clarithromycin^a

55 ± 8^c

36 ± 7^c

↔ Aged

42-50

7.3 ± 1.9^c

↓ Aged, RD

↔ LD

2.6 ± 0.5^c

↔ Aged

↑ LD

3.3 ± 0.5^c

↑ Aged, RD, LD

C: 2.8^d

HC: 3^d

C: 2.4 μg/mL^d

HC: 0.7 μg/mL^d

^aActive metabolite, 14(R)-hydroxyclarithromycin. ^bData generated for a 250-mg oral dose. ^cAt higher doses, metabolic CL saturates, resulting in increases in the percentage of urinary excretion and t_1/2 and a decrease in CL. ^dMean data for clarithromycin (C) and 14-hydroxyclarithromycin (HC), following a 500-mg oral dose given twice daily to steady state in healthy adults.

Reference: Chu SY, et al. Absolute bioavailability of Clarithromycin after oral administration in humans. Antimicrob Agents Chemother, 1992, 36:1147–1150. Fraschini F, et al. Clarithromycin clinical pharmacokinetics. Clin Pharmacokinet, 1993, 25:189–204.

Clindamycin

∼87^a

Topical: 2

93.6 ± 0.2

4.7 ± 1.3

↔ Child

1.1 ± 0.3^b

↔ RD, Child

2.9 ± 0.7

↔ Child, RD, Preg

↑ Prem

—

IV: 17.2 ± 3.5 μg/mL^c

PO: 2.5 μg/mL^d

^aClindamycin hydrochloride given orally. ^bV_area reported. ^cFollowing a 1200-mg IV dose(30-minute infusion) of clindamycin phosphate (prodrug) given twice daily to steady state in healthy male adults. ^dFollowing a single 150-mg oral dose of clindamycin hydrochloride to adults.

References: PDR54, 2000, p. 2421. Plaisance KI, et al. Pharmacokinetic evaluation of two dosage regimens of clindamycin phosphate. Antimicrob Agents Chemother, 1989, 33:618–620.

Clonazepam

98 ± 31

86 ± 0.5

↓ Neo

1.55 ± 0.28^a,b

3.2 ± 1.1

23 ± 5

PO: 2.5 ± 1.3^c

IV: 3-29 ng/mL^c

PO: 17 ± 5.4 ng/mL^c

^aCL/F reported; this value is consistent for a number of studies but is higher than the CL determined in a single study of IV administration. ^bMetabolized by CYP3A. ^cRange of C_max values following a single 2-mg IV dose (model-fitted for bolus dose) or mean following a 2-mg oral dose (tablet) given to healthy adults. Most patients, including children whose seizures are controlled by clonazepam have steady-state concentrations of 5-70 ng/mL. However, patients who do not respond and those with side effects achieve similar levels.

Reference: Berlin A, et al. Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol, 1975, 9:155–159.

Clonidine

PO: 95

TD: 60

62 ± 11

3.1 ± 1.2

↓ RD

2.1 ± 0.4

12 ± 7

↑ RD

PO: 2^a

TD: 72^a

PO: 0.8 ng/mL^a

TD: 0.3-0.4 ng/mL^a

^aMean data following a 0.1-mg oral dose given twice a day to steady state or steady-state concentration (C_ss) following a 3.5-cm² transdermal (TD) patch administered to normotensive male adults. Concentrations of 0.2-2 ng/mL are associated with a reduction in blood pressure; >1 ng/mL will cause sedation and dry mouth.

Reference: Lowenthal DT, et al. Clinical pharmacokinetics of clonidine. Clin Pharmacokinet, 1988, 14:287–310.

Clopidogrel^a

—^b

—

Clo: 98

—

Clo: 4-6

AM: 0.5^c

Clo: 0.5-1

AM: 1.0^d

Clo^d

EM: 3.8 ± 2.5 ng/mL

IM: 6.8 ± 3.6 ng/mL

PM: 18 ± 14 ng/mL

AM^d

EM: 39 ± 15 ng/mL

IM: 26 ± 11 ng/mL

PM: 24 ± 6 ng/mL

^aClopidogrel (Clo) is a prodrug that is converted to a minor unstable active metabolite (AM) via two sequential cytochrome P450-dependent reactions. The majority of the dose getsconverted rapidly to an inactive hydrolytic product by esterases. Although multiple P450isoforms contribute to the formation of AM, blood levels of AM have been associated with the CYP2C19 genotype and phenotype status, with poor metabolizers (PM) exhibiting lowerlevels, on average, than extensive metabolizers (EM). Formation of AM accounts for ≤10% of the administered dose and may be dose dependent due to saturable metabolism. ^bThe absolute bioavailability of Clo is unknown. There is one report of food greatly enhancing the systemic exposure of Clo following oral administration. ^cThe reported value may represent disappearance of high levels of metabolite formed during first-pass and not the terminal t_1/2, which should be formation limited. ^dFollowing a single 300-mg loading dose of Clo.

References: Farid NA, et al. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol, 2009, Nov 30 [Epub ahead of print]. Kim KA, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: A possible mechanism for clopidogrel resistance. Clin Pharmacol Ther, 2008, 84:236–242. Takahashi M, et al. Quantitative determination of clopidogrel active metabolite in human plasma by LC-MS/MS. J Pharm Biomed Anal, 2008, 48:1219–1224. Umemura K, et al. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemost, 2008, 6:1439–1441.

Clorazepate^a

N: 91 ± 6^a

N: <1

N: 97.5

↓ RD

↔ Obes, Aged^b

N: 0.17 ± 0.02^c

↑ Smk

↓ Hep, LD, Obes, Aged^b

N: 1.24 ± 0.09^c

↑ Obes, Preg

↔ Hep, LD, Aged

N: 93 ± 11^c

↑ Obes, Preg, Aged^b

↓ Hep, LD, Smk

N: 0.72 ± Aged^b

0.01^a,d

N: 275 ± 27 ng/mL^a,d

^aClorazepate is essentially a prodrug for nordiazepam (N). Bioavailability, T_max, and C_max values for N were derived after oral administration of clorazepate. ^bSignificantly different for male subjects only. ^cCL, V_ss, and t_1/2 values are for IV nordiazepam. ^dData for N following a 20-mg IM dose of clorazepate given to nonpregnant women.

References: Greenblatt DJ, et al. Desmethyldiazepam pharmacokinetics: Studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam. J Clin Pharmacol, 1988, 28:853–859. Rey E, et al. Pharmacokinetics of clorazepate in pregnant and non-pregnant women. Eur J Clin Pharmacol, 1979, 75:175–180.

Clozapine

55 ± 12

>95

6.1 ± 1.6

5.4 ± 3.5

12 ± 4

1.9 ± 0.8^a

546 ± 307 ng/mL^a

^aFollowing titration up to a 150-mg oral dose (tablet) given twice daily for 7 days to adult chronic schizophrenics.

References: Choc MG, et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res, 1987, 4:402–405. Jann MW, et al. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet, 1985, 10:315–333.

Codeine^a

50 ± 7^b

Negligible

11 ± 2^c

2.6 ± 0.3^c

2.9 ± 0.7

C: 1.0 ± 0.5^d

M: 1.0 ± 0.4^d

C: 149 ± 60 ng/mL^d

M: 3.8 ± 2.4 ng/mL^d

^aCodeine is metabolized by CYP2D6 (polymorphic) to morphine. Analgesic effect is thought to be due largely to derived morphine. ^bOral/IM bioavailability reported. ^cCL/F and V_area/F reported. ^dData for codeine (C) and morphine (M) following a 60-mg oral codeine dose given three times daily for 7 doses to healthy male adults.

Reference: Quiding H, et al. Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration. Eur J Clin Pharmacol, 1986, 30:673–677.

Cyclobenzaprine^a

IR: 55 (51-60)

ER: —^b

9.8 ± 3.1

↓ Aged^c

↓ LD^d

—^e

18 (8-37)^f

↑ Aged^c

↑ LD^d

IR: 3.9 ± 1.8^g

ER: 7.1 ± 1.6^h

IR: 26 ± 11 ng/mL^g

ER: 20 ± 6 ng/mL^h

^aCleared primarily by cytochrome P450-dependent metabolism; multiple isoforms involved, including CYP3A4 and CYP1A2. Both immediate-release (IR) and extended-release (ER) products available. ^bSimilar systemic exposure from a single 30-mg ER dose and three 10-mg IR doses. ^cFor both IR and ER products, systemic exposure is increased in the elderly, compared to young adults. ^dStudy in patients with mild to moderate hepatic impairment. ^eNo published value available; V_β estimated from reported mean clearance and t_1/2 = 15.3 L/kg. ^fApparent t_1/2 of ER product: 32 ± 10 hours. ^gFollowing the 10-mg IR product given three times daily to steady state in young adults. ^hFollowing a single dose of the 30-mg ER product in young adults.

References: Darwish M, et al. A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15 mg and 30 mg: A randomized, double-blind, two-period crossover study in healthy volunteers. Clin Ther, 2009, 31:108–114. Darwish M, et al. Single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults: A randomized, open-label, two-period crossover, single-centre study. Clin Drug Investig, 2008, 28:793–801. Hucker HB, et al. Physiological disposition and metabolism of cyclobenzaprine in the rat, dog, rhesus monkey, and man. Drug Metab Dispos, 1978, 6:659–672. Winchell GA, et al. Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency. J Clin Pharmacol, 2002, 42:61–69.

Cyclophosphamide^a

74 ± 22

6.5 ± 4.3

1.3 ± 0.5

↑ Child

↓ LD

↔ RD

0.78 ± 0.57

↔ Child

7.5 ± 4.0

↓ Child

↑ LD

—

121 ± 21 μM^b

^aCyclophosphamide is primarily activated by CYP2C9 to hydroxycyclophosphamide. The metabolite is further converted to the active alkylating species, phosphoramide mustard (t_1/2 = 9 hours) and nornitrogen mustard (apparent t_1/2 = 3.3 hours). Kinetic parameters are for cyclophosphamide. ^bFollowing a 600-mg/m² IV (bolus) dose given to breast cancer patients.

References: Grochow LB, et al. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet, 1979, 4:380–394. Moore MJ, et al. Variability in the pharmacokinetics of cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer. Cancer Chemother Pharmacol, 1994, 33:472–476.

Cyclosporine

SI: 28 ± 18^a,b

93 ± 2

5.7 (0.6-24)^b,c

↓ Hep, LD, Aged

↔ RD

↑ Child

4.5 (0.12-15.5)^b

↓ Aged

↑ Child

10.7 (4.3-53)^b

↔ Aged

↓ Child

NL: 1.5-2.0^d

↓ Child

NL: 1333 ± 469 ng/mL^d

SI: 1101 ± 570 ng/mL^d

^aneoral (NL) exhibits a more uniform and slightly greater (125-150%) relative oral bioavailability than the SANDIMMUNE (SI) formulation. ^bPharmacokinetic parameters based on measurements in blood with a specific assay. Data from renal transplant patients shown. ^cMetabolized by CYP3A to three major metabolites, which are subsequently biotransformed to numerous secondary and tertiary metabolites. ^dSteady-state C_max following a 344 ±122-mg/day oral dose (divided into two doses) of cyclosporine (NL, soft gelatin capsule) or a 14-mg/kg/day (range 6-22 mg/kg/day) oral dose of cyclosporine (SI) given to adult renal transplant patients in stable condition. Mean trough concentration after NL was 251 ± 116 ng/mL; therapeutic range (trough) is 150-400 ng/mL.

References: Fahr A. Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet, 1993, 24:472–495.

PDR54, 2000, pp. 2034–2035. Pollak R, et al. Cyclosporine bioavailability of Neoral and Sandimmune in white and black de novo renal transplant recipients. Neoral Study Group. Ther Drug Monit, 1999, 27:661–663. Ptachcinski RJ, et al. Cyclosporine kinetics in renal transplantation. Clin Pharmacol Ther, 1985, 38:296–300.

Cytarabine^a

<20^b

11 ± 8

13 ± 4

2.4-2.7^c

2.6 ± 0.6

—

IV, B: ∼5 μg/mL^d

IV, I: 0.05-0.1 μg/mL^d

^aCytarabine is rapidly metabolized by deamination to non-toxic uridine arabinoside. ^bLiposome formulation of cytarabine given intrathecally. Cerebrospinal fluid t_1/2 = 100-263 hours for liposome formulation (compared to 3.4 hours for intrathecal dose of free drug). ^cV_area reported. ^dC_max following a single 200-mg/m² IV bolus (IV, B) dose or steady-state plasma concentration following a 112-mg/m²/day constant-rate IV infusion (IV, I) given to patients with leukemia, malignant melanoma, or solid tumors.

References: Ho DH, et al. Clinical pharmacology of l-β-D-arabinofuranosyl cytosine. Clin Pharmacol Ther, 1971, 72:944–954. Wan SH, et al. Pharmacokinetics of l-β-D-arabinofuranosylcytosine in humans. Cancer Res, 1974, 34:392–397.

Dapsone

93 ± 8^a

5-15^b

73 ± 1

↔ RD, LD

0.60 ± 0.17^c

↔ LD, Child

↑ Neo

1.0 ± 0.1

↔ LD

22.4 ± 5.6

↔ LD, Child

SD: 2.1 ± 0.8^d

SD: 1.6 ± 0.4 μg/mL^d

MD: 3.3 μg/mL^d

^aDecreased in severe leprosy by (70-80%) estimates based on urinary recovery of radioactive dose. ^bUrine pH = 6-7. ^cUndergoes reversible metabolism to a monoacetyl metabolite; the reaction is catalyzed by NAT2 (polymorphic); also undergoes N-hydroxylation (CYP3A, CYP2C9). ^dFollowing a single 100-mg oral dose (SD) or a 100-mg oral dose given once daily to steady state (MD) in healthy adults.

References: Mirochnick M, et al. Pharmacokinetics of dapsone administered daily and weekly in human immunodeficiency virus-infected children. Antimicrob Agents Chemother, 1999, 43:2586–2591.

Pieters FA, et al. The pharmacokinetics of dapsone after oral administration to healthy volunteers. Br J Clin Pharmacol, 1986, 22:491–494.

Venkatesan K. Clinical pharmacokinetic considerations in the treatment of patients with leprosy. Clin Pharmacokinet, 1989, 16:365–386.

Zuidema J, et al. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet, 1986, 11:299–315.

Daptomycin

—^a

47 ± 12

0.14 ± 0.01

↑ RD^b

0.096 ± 0.009

↑ RD^b

7.8 ± 1.0

↑ RD^b

—

99 ± 12 μg/mL^c

^aAvailable for IV administration only. ^bChanges reported for patients with severe renal impairment. ^cC_max at the end of a 30-minute IV infusion of a 6-mg/kg dose given once daily for 7 days. No significant accumulation with multiple dosing.

References: Dvorchik BH, et al. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother, 2003, 47:1318–1323. Product information: Cubicin™ (daptomycin for injection). Lexington, MA, Cubist Pharmaceuticals, 2004.

Darunavir^a

↑ Food^b

—

1.4 ± 0.5

↔ LD^c

↔ RD^d

1.9

15 (13-21)

2.5-4^e

11-15 μg/mL^e

^aDarunavir should be taken in combination with ritonavir, a potent CYP3A and P-glycoprotein inhibitor, which profoundly increases systemic exposure to darunavir. Data reported are for combined administration of darunavir (IV or oral) with 100-mg oral ritonavir, twice daily. ^bSystemic exposure increased 42% when taken with a meal. ^cStudy in patients with mild to moderate liver impairment. ^dStudy in patients with moderate renal impairment. ^eFollowing 600-mg darunavir once daily and 100-mg ritonavir twice daily, to steady state; C_trough = 3.5 (1.6-7.4) μg/mL.

References: Drugs @FDA. Prezista label approved on 6/16/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021976s010lbl.pdf. Accessed May 17, 2010. McCoy C. Darunavir: A nonpeptidic antiretroviral protease inhibitor. Clin Ther, 2007, 29:1559–1576. Rittweger M, et al. Clinical pharmacokinetics of darunavir. Clin Pharmacokinet, 2007, 46:739–756.

Dextroamphetamine^a

—^b

Rac: 14.5^c

Rac: 23-26

Dextro: 3.4-7.7^d (Acidic urine)

Dextro: 0.23-1.71^d (Alkaline urine)

Rac: 6.11 ± 0.22

Rac: 3.5-4.2^d (Acidic urine)

Rac: 14-22^d (Alkaline urine)

Dextro: 6.8 ± 0.5^e (Uncontrolled urine pH)

Dextro: 3.1 ± 1.1^f

Dextro: 61 ± 20 ng/mL^f

^aAmphetamine is available as a racemate (Rac), dextro-isomer (Dextro), and a mixture of the two, in both immediate- and extended-release formulations. Pharmacokinetic data on both racemic and dextroamphetamine are presented. ^bAbsolute bioavailability not reported; >55% based on urine recovery of unchanged drug under acidic urinary pH conditions. ^cMeasured under uncontrolled urinary pH condition. Renal CL of amphetamine is dependent on urine pH. Acidification of urine results in increased urinary excretion, up to 55%. ^dCL/F and t_1/2following oral dose to adults is reported. ^et_1/2 in children reported. ^fFollowing a 20-mgimmediate-release oral dose given once daily for >1 week. An extended-release formulation consisting of a mixture of dextroamphetamine and amphetamine salts (ADDERALL XR) exhibits a delayed T_max of ∼7 hours.

References: Busto U, et al. Clinical pharmacokinetics of non-opiate abused drugs. Clin Pharmacokinet, 1989, 16:1–26. Helligrel ET, et al. Steady-state pharmacokinetics and tolerability of modafinil administered alone or in combination with dextroamphetamine in healthy volunteers. J Clin Pharmacol, 2002, 42:450–460. McGough JJ, et al. Pharmacokinetics of SLI381 (ADDERALL XR), an extended-release formulation of Adderall. J Am Acad Child Adolesc Psychiatry, 2003, 42:684–691.

Diazepam^a

PO: 100 ± 14

Rectal: 90

98.7 ± 0.2

↓ RD, LD, NS, Preg, Neo, Alb, Burn, Aged

↔ HTh

0.38 ± 0.06^a

↑ Alb

↓ LD

↔ Aged, Smk, HTh

1.1 ± 0.3

↑ LD, Aged, Alb

↔ RD, HTh

43 ± 13^a

↑ Aged, LD

↔ HTh

PO: 1.3 ± 0.2^b

Rectal: 1.5^b

IV: 400-500 ng/mL^b

PO: 317 ± 27 ng/mL^b

Rectal: ∼400 ng/mL^b

^aActive metabolites, desmethyldiazepam and oxazepam, formed by CYP2C19 (polymorphic) and CYP3A. ^bRange of data following a single 5- to 10-mg IV dose (15- to 30-second bolus) or mean data following a single 10-mg oral or 15-mg rectal dose given to healthy adults. A concentration of 300-400 ng/mL provides an anxiolytic effect, and >600 ng/mL provides control of seizures.

References: Friedman H, et al. Pharmacokinetics and pharmacodynamics of oral diazepam: Effect of dose, plasma concentration, and time. Clin Pharmacol Ther, 1992, 52:139–150. Greenblatt DJ, et al. Diazepam disposition determinants. Clin Pharmacol Ther, 1980, 27:301–312. PDR54, 2000, p. 1012.

Diclofenac

54 ± 2

>99.5

4.2 ± 0.9^a

↓ Aged

↔ RD, LD, RA

0.17 ± 0.11^b

↑ RA

1.1 ± 0.2

↔ RA

EC: 2.5 (1.0-4.5)^c

SR: 5.3 ± 1.5^c

EC: 2.0 (1.4-3.0) μg/mL^c

SR: 0.42 ± 0.17 μg/mL^c

^aCleared primarily by CYP2C9-catalyzed 4′-hydroxylation; urine and biliary metabolites account for 30% and 10-20% of dose, respectively. ^bV_area reported. ^cFollowing a single 50-mg enteric-coated tablet (EC) or 100-mg sustained-release tablet (SR) given to healthy adults.

References: Tracy T. Nonsteroidal antiinflammatory drugs. In: Levy RH, et al., eds. Metabolic Drug Interactions. Philadelphia, Lippincott Williams & Wilkins, 2000, pp. 457–468. Willis JV, et al. The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol, 1979, 16:405–410.

Digoxin

70 ± 13^a,c

↔ RD, MI, CHF, LTh, HTh, Aged

60 ± 11

25 ± 5

↓ RD

CL = 0.88CL_cr + 0.33^b,c

↓ LTh

↑ HTh, Neo, Child, Preg

V = 3.12CL_cr + 3.84

↓ LTh

↑ HTh

↔ CHF

39 ± 13

↓ HTh

↑ RD, CHF, Aged, LTh

↔ Obes

l-3^d

NT: 1.4 ± 0.7 ng/mL^d

T: 3.7 ± 1.0 ng/mL^d

^alanoxin tablets; digoxin solutions, elixirs, and capsules may be absorbed more completely. ^bEquation applies to patients with some degree of heart failure. If heart failure is not present, the coefficient of CL_cr is 1.0. Units of CL_cr must be mL/min/kg. ^cln the occasional patient, digoxin is metabolized to an inactive metabolite, dihydrodigoxin, by gut flora. This results in a reduced oral bioavailability. ^dFollowing an oral dose of 0.31 ± 0.19 mg/day or 0.36 ± 0.19 mg/day in patients with CHF who exhibited no signs of digitalis toxicity (NT) or signs of toxicity (T), respectively. Concentrations >0.8 ng/mL are associated with an inotropic effect. Concentrations of 1.7, 2.5, and 3.3 ng/mL are associated with a 10%, 50%, and 90% probability of digoxin-induced arrhythmias, respectively.

References: Mooradian AD. Digitalis. An update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet, 1988, 15:165–179. Smith TW, et al. Digoxin intoxication: The relationship of clinical presentation to serum digoxin concentration. J Clin Invest, 1970, 49:2377–2386.

Diltiazem^a

38 ± 11

78 ± 3

11.8 ± 2.2^b

↔ Aged

↓ RD

3.3 ± 1.2

↔ Aged

↓ RD

4.4 ± 1.3^c

↔ RD, Aged

4.0 ± 0.4^d

151 ± 46 ng/mL^d

^aActive metabolites, desacetyldiltiazem (t_1/2 = 9 ± 2 hours) and N-desmethyldiltiazem (t_1/2 = 7.5 ± 1 hour). Formation of desmethyl metabolite (major pathway of CL) catalyzed primarily by CYP3A. ^bMore than a 2-fold decrease with multiple dosing. ^ct_1/2 for oral dose is 5-6 hours; does not change with multiple dosing. ^dFollowing a single 120-mg oral dose to healthy adults.

Reference: Echizen H, et al. Clinical pharmacokinetics of verapamil, nifedipine, and diltiazem. Clin Pharmacokinet, 1986, 11:425–449.

Diphenhydramine

72 ± 26

1.9 ± 0.8

↔ LD

78 ± 3

↔ LD

6.2 ± 1.7^a

↔ LD

↑ Child

↓ Aged

4.5 ± 2.8^a,b

↔ LD

8.5 ± 3.2^a

↑ LD, Aged

↓ Child

PO: 2.3 ± 0.64^c

IV: ∼230 ng/mL^c

PO: 66 ± 22 ng/mL^c

^aIncreased CL, decreased V, and no change in t_1/2 in Asians, presumably due to decreased plasma protein binding. ^bV_area reported. ^cFollowing a single 50-mg dose of diphenhydramine hydrochloride (44-mg base) given IV or orally to fasted healthy adults. Levels >25 ng/mL provide antihistaminic effect, whereas levels >60 ng/mL are associated with drowsiness and mental impairment.

Reference: Blyden GT, et al. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol, 1986, 26:529–533.

Docetaxel^a

—

2.1 ± 0.2

22.6 ± 7.7 L/hr/m²

↓ LD^b

72 ± 24 L/m²

13.6 ± 6.1

—

2.4 ± 0.9 μg/mL^c

^aData from male and female patients treated for cancer. Metabolized by CYP3A and excreted into bile. Parenteral administration. ^bMild to moderate liver impairment. ^cFollowing an IV infusion of 85 mg/m² over 1.6 hours.

References: Clarke SJ, et al. Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet, 1999, 36:99–114. Extra JM, et al. Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res, 1993, 53:1037–1042. PDR54, 2000, p. 2578.

Donepezil^a

—^b

10.6 ± 2.7

92.6 ± 0.9^c

2.90 ± 0.74^d

↓ LD,^e

↔ RD

14.0 ± 2.42^d

↑ Aged

59.7 ± 16.1^d

↑ Aged

3-4^f

30.8 ± 4.2 ng/mL^f

^aData from young, healthy male, and female subjects. No significant gender differences. Metabolized by CYP2D6, CYP3A4, and UGT. ^bAbsolute bioavailability is unknown, but the oral dose reportedly is well absorbed. ^cA fraction bound value of 96% also has been reported. ^dCL/F, V_ss/F, and t_1/2 reported for oral dose. ^eCL/F reduced slightly (∼20%), alcoholic cirrhosis. ^fFollowing a 5-mg oral dose given once daily to steady state.

References: Ohnishi A, et al. Comparison of the pharmacokinetics of E2020, a new compound for Alzheimer's disease, in healthy young and elderly subjects. J Clin Pharmacol, 1993, 33:1086–1091. PDR54, 2000, p. 2323.

Doxazosin^a

Y: 65 ± 14

E: 68 ± 16

GITS: F_rel = 59 ± 12

Y: 1.26 ± 0.27

E: 2.25 ± 1.42

↓ LD^b

Y: 1.0 ± 0.1

E: 1.7 ± 1.0

20.5 ± 6.1^c,d

GITS: 19 ± 4^d

↔ LD^b

3.9 ± 1.2^d

GITS: 9 ± 5^d

67 ± 19 ng/mL^d

GITS: 28 ± 12 ng/mL^d

^aCleared primarily by cytochrome P450-dependent metabolism. Where indicated, data for young (Y) and elderly (E) normotensive adults are reported. Also reported are data for a gastrointestinal sustained-release device (GITS); oral bioavailability relative to standard formulation (F_rel). ^bStudy in patients with mild to moderate liver impairment; AUC increased 43%. ^cShorter t_1/2 following IV dosing reported; (Y) 10 ± 1 hour, (E) 12 ± 5 hour; attributed to inadequate duration of blood sampling. ^dFollowing an 8-mg dose of standard formulation or GITS, once daily, to steady state in young and elderly normotensive volunteers.

References: Chung M, et al. Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation. Br J Clin Pharmacol, 1999, 48:678–687. Elliott HL, et al. Pharmacokinetic overview of doxazosin. Am J Cardiol, 1987, 59:78G–81G. Penenberg D, et al. The effects of hepatic impairment on the pharmacokinetics of doxazosin. J Clin Pharmacol, 2000, 40:67–73. Vincent J, et al. The pharmacokinetics of doxazosin in elderly normotensives. Br J Clin Pharmacol, 1986, 21:521–524.

Doxepin^a

30 ± 10^b

∼0

82 (75-89)

14 ± 3^c

24 ± 7^c,d

18 ± 5

D: 0.5-1

DD: 4-12

D: 28 ± 11 ng/mL^e

DD: 39 ± 19 ng/mL^e

^aThe active metabolite, desmethyldoxepin, has a longer t_1/2 (37 ± 15 hours). ^bCalculated from results of oral administration only, assuming complete absorption, elimination by the liver, hepatic blood flow of 1.5 L/min, and equal partition between plasma and erythrocytes. ^cCalculated assuming F = 0.30. ^dV_area reported. ^eTrough concentrations of doxepin (D) and desmethyldoxepin (DD) following a 150-mg oral dose given once daily for 3 weeks to patients with depression. Peak/trough ratio <2.

Reference: Faulkner RD, et al. Multiple-dose doxepin kinetics in depressed patients. Clin Pharmacol Ther, 1983, 34:509–515.

Doxorubicin^a

666 ± 339 mL/min/m²

↑ Child

↓ LD, Obes

682 ± 433

L/m²

↔ LD

26 ± 17^b

↔ RD

↑ LD

—

High^c

D: ∼950 ng/mL

DL: 30-1008 ng/mL

Low^c

D: 6.0 ± 3.2 ng/mL

DL: 5.0 ± 3.5 ng/mL

^aActive metabolites; t_1/2 for doxorubicinol is 29 ± 16 hours. ^bProlonged when plasma bilirubin concentration is elevated; undergoes biliary excretion. ^cMean data for doxorubicin (D) and range of data for doxorubicinol (DL). High: a single 45- to 72-mg/m² high-dose 1-hour IV infusion given to patients with small cell lung cancer. Low: continuous IV infusion at a rateof 3.9 ± 0.65 mg/m²/day for 12.4 (2-50) weeks to patients with advanced cancer.

References: Ackland SP, et al. Pharmacokinetics and pharmacodynamics of long-termcontinuous-infusion doxorubicin. Clin Pharmacol Ther, 1989, 45:340–347. Piscitelli SC, et al. Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther, 1993, 53:555–561.

Doxycycline

41 ± 19

88 ± 5

↓ RD^a

0.53 ± 0.18

↓ HL, Aged

↔ RD

0.75 ± 0.32

↓ HL, Aged

16 ± 6

↔ RD, HL, Aged

Oral: 1-2^b

IV: 2.8 μg/mL^b

PO: 1.7-2 μg/mL^b

^aDecreases in plasma protein binding to 71 ± 3% in patients with uremia. ^bMean data following a single 100-mg IV dose (1-hour infusion) or range of mean data following a 100-mg oral dose given to adults.

Reference: Saivin S, et al. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet, 1988, 15:355–366.

Dronabinol^a

10-20

Trace

∼97

7.8 ± 1.9^b

↑ Chronic^c

8.9 ± 4.2

α: 2.8 ± 1.8

β: 20 ± 4^d

↔ Chronic^e

2.5 (0.5-4.0)^f

3.0 ± 1.8 ng/mL^f

^aCleared primarily by cytochrome P450-dependent metabolism; evidence suggests polymorphic CYP2C9 is a major contributor. ^bSomewhat lower values (2.8-3.5 mL/min/kg) also were reported, but a higher systemic clearance is most consistent with the low oral bioavailability. ^cStudy in long-term users of THC. ^dExhibits biphasic kinetics; the longer terminal elimination phase most likely represents redistribution from fatty tissue. ^eNo change in terminal (redistribution) t_1/2. ^fFollowing a 5-mg dose given twice daily to steady state.

References: Bland TM, et al. CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: Kinetics, pharmacogenetics and interaction with phenytoin. Biochem Pharmacol, 2005, 70:1096–1103. Drugs@FDA. Marinol label approved on 6/21/06. http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018651s025s026lbl.pdf. Accessed May 17, 2010. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet, 2003, 42:327–360. Hunt CA, et al. Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther, 1980, 215:35–44. Wall ME, et al. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther, 1983, 34:352–363.

Duloxetine^a

42.8 (18.5-71.2)

↓ Smk^b

—

>90

10.6 ± 2.4

↓ LD^c

↓ RD^d

7.0 ± 1.3

9.3 (6.4-12)

↑ LD^c

↔ RD^d

4.5 (2.5-6)^e

32.9 ng/mL^e

^aCleared primarily by CYP1A2- and CYP2D6-dependent metabolism. ^b∼30% lower bioavailability based on population pharmacokinetic analysis; no dose adjustment recommended. ^cA 5-fold increase in oral AUC in patients with moderate liver impairment. ^dA 2-fold increase in oral AUC in patients with end-stage RD receiving intermittent dialysis. ^eFollowing a single 60-mg oral dose.

References: Lobo ED, et al. In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine. Clin Pharmacokinet, 2008, 47:191–202. Lobo ED, et al. Population pharmacokinetics of orally administered duloxetine in patients: Implications for dosingrecommendation. Clin Pharmacokinet, 2009, 48:189–197. Drugs@FDA. Cymbalta label approved on 6/16/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021427s030lbl.pdf. Accessed May 17, 2010.

Dutasteride^a

60 (40-94)

—

—^b

840^c

1 (1-3)^d

38 ± 13 ng/mL^d

^aDutasteride is cleared primarily by CYP3A-dependent metabolism. ^bCL/F = 0.20-0.37mL/min/kg, and V/F = 4.3-7.1 L/kg; calculated from steady-state (24 wk) serum concentrations. ^cTerminal t_1/2 reported. ^dFollowing a 0.5-mg dose given once daily to steady state (24 weeks).

References: Clark RV, et al. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5-alpha-reductase inhibitor. J Clin Endocrinol Metab, 2004, 89:2179–2178. Keam SJ, et al. Dutasteride: A review of its use in the management of prostate disorders. Drugs, 2008, 68:463–485.

Efavirenz^a

—^b

↑ Food

99.5-99.75

3.1 ± 1.2^c

↔ Child^d

—

SD: 52-76^c

MD: 40-55^c

4.1 ± 1.7^e

4.0 ± 1.7 μg/mL^e

^aData from patients with HIV infection. No significant gender differences. Metabolized primarily by CYP2B6 and to a lesser extent by CYP2A6 and through N-glucuronidation. ^bAbsolute oral bioavailability is unknown. Oral AUC increased 50% with high-fat meal. ^cSingle dose (SD) data reported for CL/F and both SD and multiple dose (MD) data for t_1/2. Efavirenz is a weak inducer of CYP3A4 and its own metabolism. ^d3-16 years of age, no difference in weight-adjusted CL/F compared to adult. ^eFollowing a 600-mg oral dose given daily to steady state.

References: Adkins JC, et al. Efavirenz. Drugs, 1998, 56:1055–1064. PDR54, 2000, p. 981. Villani P, et al. Pharmacokinetics of efavirenz (EFV) alone and in combination therapy with nelfinavir (NFV) in HIV-1 infected patients. Br J Clin Pharmacol, 1999, 48:712–715.

Eletriptan^a

∼50

↑ Food^b

9 (7-12)^c

5.6 (3.7-6.7)^c

↓ LD^d

2.0 (1.4-2.4)^c

4.1 (2.8-5.5)^c

↑ LD^e

MF: 0.75-1.5^e

M: 2.0-2.8^e

57-115 ng/mL^f

^aCleared primarily by CYP3A-dependent metabolism. ^bSystemic exposure increased 20-30% with high-fat meal. ^cData from 50-μg/kg IV dose reported; lack of dose proportionality for oral AUC between 20- and 40- or 80-mg doses. ^dStudy in patients with mild to moderate hepatic impairment. ^eFollowing single 20- to 80-mg oral doses; MF: migraine-free period; M: during a migraine attack. ^fRange of mean values from different studies following a single 30-mg oral dose.

References: McCormack PL, et al. Eletriptan: A review of its use in the acute treatment of migraine. Drugs, 2006, 66:1129–1149. Milton KA, et al. Pharmacokinetics, pharmacodynamics, and safety of the 5-HT(1B/1D) agonist eletriptan following intravenous and oral administration. J Clin Pharmacol, 2002, 42:528–539. Drugs@FDA. Relpax label approved on 12/26/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21016_relpax_lbl.pdf. Accessed May 17, 2010.

Emtricitabine^a

Cap: 93^b (78-99)

Sol: 75^b

73 ± 4^c

4.4 ± 0.8^c

↓ RD^d

3.5 ± 0.8^c

9.0 ± 0.9^c

↑ RD^d

2.0 ± 1.0^e

1.7 ± 0.8 μg/mL^e

^aCleared primarily by renal excretion.^bData for capsule (Cap) and solution (Sol) formulations presented. ^cData from a 200-mg IV dose, as filed in NDA; V_area reported. ^dStudy in patients with mild to severe renal impairment and end-stage RD; CL reduced in parallel with decline in CL_cr; removed by hemodialysis. ^eFollowing 200 mg, given once daily, to HIV-infected adults.

References: Modrzejewski KA, et al. Emtricitabine: A once-daily nucleoside reverse transcriptase inhibitor. Ann Pharmacother, 2004, 38:1006–1014. Drugs@FDA. Emtriva NDA approved on 7/2/03. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-500_Emtriva_BioPharmr_P2.pdf. Accessed May 17, 2010.

Enalapril^a

41 ± 15

↓ LD

88 ± 7^b

↓ LD

50-60

4.9 ± 1.5^c

↓ RD, Aged, CHF, Neo

↑ Child

↔ Fem

1.7 ± 0.7^c

11^d

↑ RD, LD

3.0 ± 1.6^e

69 ± 37 ng/mL^e

^aHydrolyzed by esterases to the active metabolite, enalaprilic acid (enalaprilat); except when noted, pharmacokinetic values and disease comparisons are for enalaprilat, following oral enalapril administration. ^bFor IV enalaprilat. ^cCL/F and V_ss/F after multiple oral doses of enalapril. Values after single IV dose of enalaprilat are misleading because binding to ACE leads to a prolonged t_1/2, which does not represent a significant fraction of the CL upon multiple dosing. ^dEstimated from the approach to steady state during multiple dosing. ^eMean values for enalaprilat following a 10-mg enalapril oral dose given daily for 8 days to healthy young adults. The EC₅₀ for ACE inhibition is 5-20 ng/mL enalaprilat.

References: Lees KR, et al. Age and the pharmacokinetics and pharmacodynamics of chronic enalapril treatment. Clin Pharmacol Ther, 1987, 41:597–602. MacFadyen RJ, et al. Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships. An overview. Clin Pharmacokinet, 1993, 25:274–282.

Enoxaparin^a

SC: 92

—^b

—

0.3 ± 0.1^c

↓ RD

0.12 ± 0.04^c

↔ RD

3.8 ± 1.3^d

↑ RD

3^e

ACLM: 145 ± 45 ng/mL^e

BCLM: 414 ± 87 ng/mL^e

^aEnoxaparin consists of low-molecular-weight heparin fragments of varying lengths. ^b43% is recovered in urine when administered as ⁹⁹Tc-labeled enoxaparin; 8-20% anti-factor Xa activity. ^cF, CL/F, and V_area/F for SC dose measured by functional assay for anti-factor Xa activity. ^dMeasured by functional assay of anti-factor Xa activity. Using anti-IIa activity or displacement binding assay gives a t_1/2 of ~1-2 hours. ^eFollowing a single 40-mg SC dose to healthy adult subjects. High-affinity antithrombin III molecules: ACLM, above-critical-length molecules (anti-factor Xa and IIa activity); BCLM, below-critical-length molecules (anti-factor Xa activity).

References: Bendetowicz AV, et al. Pharmacokinetics and pharmacodynamics of a low molecular weight heparin (enoxaparin) after subcutaneous injection, comparison with unfractionated heparin—A three way cross over study in human volunteers. Thromb Haemost, 1994, 71:305–313. PDR54, 2000, p. 2561.

Entacapone^a

42 ± 9^b

↑ LD^c

Negligible

10.3 ± 1.74

↔ RD, LD

0.40 ± 0.16

0.28 ± 0.06^d

0.8 ± 0.2^e

4.3 ± 2.0 μg/mL^e

^aData from healthy male subjects. Eliminated primarily by biliary excretion. ^bThe bioavailability of entacapone appears to be dose dependent (increases from 29-46% over a 50- to 800-mg dose range). ^cIncreased bioavailability, moderate hepatic impairment with cirrhosis. ^dValue represents the t_1/2 for the initial distribution phase, during which 90% of a dose is eliminated. The terminal t_1/2 is 2.9 ± 2.0 hours. ^eFollowing a single 400-mg oral dose. No accumulation with multiple dosing.

References: Holm KJ, et al. Entacapone. A review of its use in Parkinson's disease. Drugs, 1999, 58:159–177. Keränen T, et al. Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone. Eur J Clin Pharmacol, 1994, 46:151–157.

Eplerenone^a

—

7^b

33-60^c

2.4^d

↓ CHF, LD

0.6-1.3^d

4-6

1.8 ± 0.7^e

1.0 ± 0.3 μg/mL^e

^aEplerenone is converted (reversibly) to an inactive ring-open hydroxy acid. Both eplerenone (E) and the hydroxy acid (EA) circulate in plasma; concentrations of E are much higher than EA. Irreversible metabolism is catalyzed predominantly by CYP3A4. Data for E in healthy male and female volunteers reported; no significant gender differences. ^bRecovered as E and EA following an oral dose. ^cProtein binding is concentration dependent over the therapeutic range; lower at the highest concentration. ^dCL/F and V_ss/F reported. ^eFollowing a 50-mg oral dose given once daily for 7 days.

References: Clinical Pharmacology and Biopharmaceutics Review. Application 21-437/S-002. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra.cfm. Accessed July 9, 2010. Cook CS, et al. Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans. Drug Metab Dispos, 2003, 31:1448–1455. Product information: Inspra^™ (eplerenone tablets). Chicago, IL, Pfizer, 2004.

Erlotinib^a

59 (55-66)

↑ Food^b

—

93 (92-95)

1.0 ± 0.4^c

↑ Smk^d

↔ LD^e

1.2 ± 0.25^f

36^g

2-4^h

1.1-1.7 μg/mL^h

^aErlotinib is cleared primarily by CYP3A- and CYP1A2-dependent metabolism. ^bBioavailability increases to ~100% when taken with a meal; not recommended because food effect is highly variable. ^cCalculated from a 25-mg IV dose; in a population pharmacokinetic study of 150 mg, once daily, CL/F = 0.98 mL/min/kg. ^dSystemic exposure reduced by half compared to nonsmokers. ^eStudy in patients with moderate LD; no data for severe hepatic impairment. ^fCalculated from a 25-mg IV dose; in a population pharmacokinetic study of150-mg once daily, V/F = 3.5 L/kg. ^gMedian t_1/2 in a patient population receiving 150-mg orally once daily; a shorter t_1/2 of 13 hours was reported for a single 25-mg IV dose. ^hFollowing 150-mg given once daily to steady state.

References: Frohna P, et al. Evaluation of the absolute oral bioavailability and bioequivalence of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects. J Clin Pharmacol, 2006, 46:282–290. Lu JF, et al. Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther, 2006, 80:136–134. Drugs@FDA. Tarceva NDA and label; label approved on 4/27/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva.cfm. Accessed May 17, 2010.

Ertapenem^a

IM: 92 (88-95)

SC: 99 ± 18

44 ± 15^b

84-96^c

0.42 ± 0.05

↓ RD^d

0.12 ± 0.02

3.8 ± 0.5

IM: 2.2 ± 0.9^e

SC: 2.7 ± 1.1^e

IV: 155 ± 22 μg/mL^e

IM: 71 ± 16 μg/mL^e

SC: 43 ± 29 μg/mL^e

^aCleared primarily by the kidney; developed for parenteral administration; data for a single 1-g dose reported. ^bUndergoes renal metabolism to an open-ring metabolite; the kidney is responsible for ~80% of the total body clearance. ^cProtein binding is concentration dependent; 96% at 10 μg/mL and 84% at 300 μg/mL. ^dDrug clearance declines in rough proportion to CL_cr. ^eFollowing a single 1-g dose; the IV dose was given over a 30-minute constant-rate infusion.

References: Frasca D, et al. Pharmacokinetics of ertapenem following intravenous and subcutaneous infusions in patients. Antimicrob Agents Chemother, 2009, Nov 23. [Epub ahead of print]. Majumdar AK, et al. Pharmacokinetics of ertapenem in healthy young volunteers. Antimicrob Agents Chemother, 2002, 46:3506–3511. Musson DG, et al. Pharmacokinetics of intramuscularly administered ertapenem. Antimicrob Agents Chemother, 2003, 47:1732–1735. Nix DE, et al. Pharmacokinetics and pharmacodynamics of ertapenem: An overview for clinicians. J Antimicrob Chemother, 2004, 53(suppl):ii23–ii28.

Erythromycin

35 ± 25^a

↓ Preg^b

12 ± 7

84 ± 3^c

↔ RD

9.1 ± 4.1^d

↔ RD

0.78 ± 0.44

↑ RD

1.6 ± 0.7

↑ LD

↔ RD

B: 2.1-3.9^e

S: 2-3^e

B: 0.9-3.5 μg/mL^e

S: 0.5-1.4 μg/mL^e

^aValue for enteric-coated erythromycin base. ^bDecreased concentrations in pregnancy possibly due to decreased bioavailability (or increased CL). ^cErythromycin base. ^dErythromycin is a CYP3A substrate; N-demethylation. It also is transported by P-glycoprotein, which may contribute to biliary excretion of parent drug and metabolites. ^eRange of mean values from studies following a 250-mg oral enteric-coated free base in a capsule (B) given four times daily for 5-13 doses or a 250-mg film-coated tablet or capsule of erythromycin stearate (S) given four times daily for 5-12 doses.

Reference: Periti P, et al. Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (part I). Clin Pharmacokinet, 1989, 16:193–214.

Escitalopram, Citalopram^a

—

Rac: 80 ± 13

Es: 8

Rac: 10.5 ± 1.4

Es: 56

Rac: 80

Es: 8.8 ± 3.2^b,c

Rac: 4.3 ± 1.2^b

↓ Aged, LD^d

Es: 15.4 ± 2.4^c

Rac: 12.3 ± 2.3

Es: 22 ± 6^b

Rac: 33 ± 4^b

↑ Aged, LD,^d RD^e

—

Rac/Es: 4-5^f

Es: 21 ± 4 ng/mL^f

Rac: 50 ± 9 ng/mL^f

^aEscitalopram is the active S-enantiomer of racemic citalopram. Pharmacokinetic data after dosing of escitalopram (Es) and citalopram racemate (Rac) are reported. No significant gender differences. Citalopram is metabolized by CYP2C19 (polymorphic) and CYP3A4 to desmethylcitalopram. ^bData from CYP2C19 extensive metabolizers. CYP2C19 poor metabolizers exhibit a lower (~44%) CL/F and longer t_1/2 than extensive metabolizers. ^cCL/F and V/F for Es reported. ^dAlcoholic, viral, or biliary cirrhosis. ^eModerate renal impairment. ^fFollowing a single 40-mg (Rac) or 20-mg (Es) oral dose.

References: Gutierrez MM, et al. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther, 2003, 25:1200–1210. Joffe P, et al. Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects. Eur J Clin Pharmacol, 1998, 54:237–242. PDR58, 2004, pp. 1292, 1302–1303. Sidhu J, et al. Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality, 1997, 9:686–692. Sindrup SH, et al. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit, 1993, 15:11–17.

Esomeprazole^a

Es: 89 (81-98)^b

Rac: 53 ± 29^b

Es/Rac: <1

Es/Rac: 95-97

Es: 4.1 (3.3-5.0)^c,d

Rac: 7.5 ± 2.7^c

↓ LD^e

Es: 0.25 (0.23-0.27)

Rac: 0.34 ± 0.09

Es: 0.9 (0.7-1.0)^d

Rac: 0.7 ± 0.5

↑ LD^e

Es: 1.5 (1.3-1.7)^f

Rac, EM: ~1^g

Rac, PM: ~3-4^g

Es: 4.5 (3.8-5.7) μM^f

Rac, EM: 0.68 ±

0.43 μM^g

Rac, PM: 3.5 ± 1.4 μM^g

^aEsomeprazole is the S-enantiomer of omeprazole. Both esomeprazole (Es) and racemic omeprazole (Rac) are available. Data for both formulations are reported. ^bBioavailability determined after multiple dosing. Lower Es values 64% (54-75%) reported for single dose. ^cThe metabolic CL of the Es is slower than that of the R-enantiomer. Both Es and Rac are metabolized by CYP2C19 (polymorphic) and CYP3A4. CL of Es and Rac is decreased and t_1/2 increased in CYP2C19 poor metabolizers. ^dFollowing a single 40-mg IV dose. CL of Es decreases and t_1/2 of Es increases with multiple dosing. ^eReduced CL and increased t_1/2 in patients with severe (Childs-Pugh class C) hepatic impairment. ^fFollowing a 40-mg oral dose of Es given once daily for 5 days to healthy subjects of unspecified CYP2C19 phenotype. ^gFollowing a 20-mg oral dose of Rac given twice daily for 4 days to healthy subjects phenotyped as CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM).

References: Andersson T, et al. Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet, 2001, 40:411–426. Chang M, et al. Interphenotype differences in disposition and effect on gastrin levels of omeprazole—Suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol, 1995, 39:511–518.

Eszopiclone,^a Zopiclone

—

Es: <10

Es: 52-59

—^b

—^c

Es: 7.2 ± 1.3

Es: ↔ RD^d

Es: ↑ LD^e

Es: 1 (0.4-2.1)

Es: 39.8 ± 8.6 ng/mL^f

^aEszopiclone is the (S)-isomer of zopiclone. Pharmacokinetic data after dosing of eszopiclone (Es) is shown. Es is metabolized extensively by CYP3A4 and CYP2E1. ^bCL/F following a15-mg oral dose of zopiclone is 2.7 mL/min/kg for Es and 4.4 mL/min/kg for racemic zopiclone. ^cV/F following a 15-mg oral dose of racemic zopiclone is 1.4 L/ kg for eszopiclone and 2 L/kg for racemic zopiclone. ^dStudy in mild, moderate, and severe RD. ^eIn patients with severe hepatic impairment. ^f Following 3-mg Es given once daily to steady state.

References: Drugs@FDA. Lunesta label approved on 04/06/09. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021476s012lbl.pdf. Accessed July 9, 2010. Najib J. Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther, 2006, 28:491–516.

Ethambutol

77 ± 8

79 ± 3

6-30

8.6 ± 0.8

1.6 ± 0.2

3.1 ± 0.4

↑ RD

2-4^a

2-5 μg/mL^a

^aFollowing a single 800-mg oral dose to healthy subjects. Concentrations >10 μg/mL can adversely affect vision. No accumulation with once-a-day dosing in patients with normal renal function.

Reference: Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet, 1984, 9:511–544.

Exenatide^a

SC: ~100

—

8.1^b

↓ RD

0.1^c

1.5 (0.9-2.0)

↑ RD

2 (1-3)^c

821 ± 500 pg/mL^d

^aExenatide is a synthetic peptide cleared primarily by the kidney through filtration, reabsorption, and proteolytic degradation. ^bCL/F after SC injection reported. ^cV_area/F after SC injection reported. ^dFollowing a 10-μg SC injection.

References: Linnebjerg H, et al. Effects of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol, 2007, 64:317–327.

Ezetimibe^a

—

>90^b

6.6^c

↓ Aged, RD, LD

1.5^c

28-30^d

1^e

122 ng/mL^e

^aEzetimibe is extensively metabolized to a glucuronide, which is more active than ezetimibe in inhibiting cholesterol absorption. Clinical effects are related to the total plasma concentration of ezetimibe and ezetimibe–glucuronide, with ezetimibe concentrations being only 10% of the total. ^bFor ezetimibe and ezetimibe–glucuronide. ^cCL/F and a volume for the central compartment (V_c/F) for total (unconjugated and glucuronide conjugate) ezetimibe reported. ^dEzetimibe undergoes significant enterohepatic recycling, leading to multiple secondary peaks. An effective t_1/2 is estimated. ^eTotal (unconjugated and glucuronide conjugate) ezetimibe following a 10-mg oral dose given once daily for 10 days.

References: Mauro VF, et al. Ezetimibe for management of hypercholesterolemia. Ann Pharmacother, 2003, 37:839–848. Patrick JE, et al. Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. Drug Metab Dispos, 2002, 30:430–437. PDR58, 2004, pp. 3085–3086.

Famotidine^a

37 (20-66)

65-80

4.3-6.9^b

↓ Aged, RD, Neo^c

1.1-1.4

2.5-4.0

↑ RD

2.3 (1-4)

76-104 ng/mL^d

^aCleared primarily by the kidney. ^bRenal clearance after IV administration was ~4.3 mL/min/kg. ^cThe pharmacokinetics of IV famotidine were similar in children >1 year of age and adults. ^dFollowing a single 40-mg oral dose.

References: Krishna DR, et al. Newer H2-receptor antagonists. Clinical pharmacokinetics and drug interaction potential. Clin Pharmacokinet, 1988, 15:205–215. Maples HD, et al. Famotidine disposition in children and adolescents with chronic renal insufficiency. J Clin Pharmacol, 2003, 43:7–14. Wenning LA, et al. Pharmacokinetics of famotidine in infants. Clin Pharmacokinet, 2005, 44:395–406.

Felodipine^a

15 ± 8

↔ Aged, Cirr

↑ Food

99.6 ± 02

↓ RD, LD

↔ Aged

12 ± 5^b

↓ Aged, LD, CHF^c

10 ± 3

↔ Aged

↓ LD

14 ± 4

↑ Aged, CHF^c

↔ LD

IR: 0.9 ± 0.4^d

ER: 3.7 ± 0.9^d

IR: 34 ± 26 nM^d

ER: 9.1 ± 7.3 nM^d

^aRacemic mixture; S-(–)-enantiomer is an active Ca⁺² channel blocker; different enantiomer pharmacokinetics result in S-(–)-enantiomer concentrations about 2-fold higher than those ofR-(+)-isomer. ^bUndergoes significant CYP3A-dependent first-pass metabolism in the intestine and liver. ^cMay be age related rather than CHF related. ^dFollowing a 10-mg oral immediate-release (IR) or extended-release (ER) tablet given twice daily to steady state in healthy subjects. EC₅₀ for diastolic pressure decrease is 8 ± 5 nM in patients with hypertension.

Reference: Dunselman PH, et al. Felodipine clinical pharmacokinetics. Clin Pharmacokinet, 1991, 21:418–430.

Fenofibrate^a

—^b

↑ Food

0.1-10^c

>99

0.45^d

↓ RD

0.89^d

20-27

↑ RD

IR: 6-8^e

Mic: 4-6^f

IR: 8.6 ± 0.9 μg/mL^e

Mic: 10.8 ± 0.6 μg/mL^f

^aFenofibrate is a prodrug that is hydrolyzed by esterases to fenofibric acid, the pharmacologically active compound. All values reported are for fenofibric acid. ^bAbsolute bioavailability is not known. Recovery of radiolabeled dose in urine as fenofibric acid and its glucuronide is 60%. Immediate-release (IR) tablet and micronized (Mic) capsule are bioequivalent. Bioavailability is increased when taken with a standard meal. ^cRecovery following oral dose. ^dCL/F and V/F reported. ^eFollowing a 300-mg IR fenofibrate tablet given once daily to steady state. ^fFollowing a 200-mg Mic capsule given once daily to steady state.

References: Balfour JA, et al. Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia. Drugs, 1990, 40:260–290. Miller DB, et al. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet, 1998, 34:155–162.

Fentanyl

TM: ~50

84 ± 2

13 ± 2^a

↓ Aged

↔ Prem,

Child

↑ Neo

4.0 ± 0.4

3.7 ± 0.4

↑ CPBS, Aged, Prem

↔ Child

TD: 35 ± 15^b

TM: 0.4 (0.3-6)^b

TD: 1.4 ± 0.5 ng/mL^b

TM: 0.8 ± 0.3 ng/mL^b

^aMetabolically cleared primarily by CYP3A to norfentanyl and hydroxy metabolites. ^bFollowing a 5-mg transdermal (TD) dose administered at 50 μg/hr through a DURAGESIC system or a single 400-μg transmucosal (TM) dose. Postoperative and intraoperative analgesia occurs at plasma concentrations of 1 ng/mL and 3 ng/mL, respectively. Respiratory depression occurs >0.7 ng/mL.

References: Olkkola KT, et al. Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children. Clin Pharmacokinet, 1995, 28:385–404.

PDR54, 2000, pp. 405, 1445.

Fexofenadine^a

—^b

60-70

9.4 ± 4.2^c

—

14 ± 6^c

↑ RD^d

↔ LD

1.3 ± 0.6^e

286 ± 143 ng/mL^e

^aData from healthy adult male subjects. ^bAbsolute bioavailability is unknown. Negligible metabolism with 85% of a dose recovered in feces unchanged; a substrate for hepatic and intestinal uptake and efflux transporters. ^cCL/F and t_1/2 reported for oral dose. ^dMild renal impairment. ^eFollowing a 60-mg oral dose twice a day to steady state.

References: Markham A, et al. Fexofenadine. Drugs, 1998, 55:269–274; discussion 275–276. Robbins OK, et al. Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers. Biopharm Drug Dispos, 1998, 19:455–463.

Finasteride

63 ± 21

2.3 ± 0.8

↔ RD, Aged

1.1 ± 0.2

7.9 ± 2.5

↔ RD, Aged

1-2^a

37 (27-49) ng/mL^a

^aFollowing a single 5-mg oral dose given to healthy adults. Drug accumulates 2-fold with once-daily dosing.

Reference: Sudduth SL, et al. Finasteride: The first 5α-reductase inhibitor. Pharmacotherapy, 1993, 13:309–325; discussion 325–329.

Flecainide^a

70 ± 11

43 ± 3

61 ± 10

↓ MI

5.6 ± 1.3^b

↓ RD, LD, CHF

↑ Child

4.9 ± 0.4^c

↑ Cirr

11 ± 3^b

↑ RD, LD, CHF

↓ Child

~3 (l-6)^d

458 ± 100 ng/mL^d

^aRacemic mixture; enantiomers exert similar electrophysiological effects. ^bMetabolized by CYP2D6 (polymorphic); except for a shortened elimination t_1/2 and nonlinear kinetics in extensive metabolizers, CYP2D6 phenotype had no significant influence on flecainide pharmacokinetics or pharmacodynamics. ^cV_area reported. ^dFollowing a 100-mg oral dose given twice daily for 5 days in healthy adults. Similar levels for CYP2D6 extensive and poor metabolizers.

Reference: Funck-Brentano C, et al. Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: Contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone. Clin Pharmacol Ther, 1994, 55:256–269.

Fluconazole

>90

75 ± 9

11 ± 1

0.27 ± 0.07

↔ AIDS, Neo

↓ RD, Prem

0.60 ± 0.11

↔ RD

↑ Prem, Neo

32 ± 5

↑ LD, RD, Prem

↓ Child

1.7-4.3^a

10.6 ± 0.4 μg/mL^a

^aFollowing a 200-mg oral dose given twice a day for 4 days to healthy adults.

References: Debruyne D, et al. Clinical pharmacokinetics of fluconazole. Clin Pharmacokinet, 1993, 24:10–27.

Varhe A, et al. Effect of fluconazole dose on the extent of fluconazole-triazolam interaction. Br J Clin Pharmacol, 1996, 42:465–470.

Fludarabine^a

—

24 ± 3

—

3.7 ± 1.5

↓ RD

2.4 ± 0.6

10-30

—

0.57 μg/mL^b

^aData from adult male and female cancer patients following IV administration. Fludarabine is rapidly dephosphorylated to 2-fluoro-arabinoside-A (F-ara-A), transported into cells, and phosphorylated to the active triphosphate metabolite. Pharmacokinetics of F-ara-A are reported. ^bFollowing a single 25-mg/m² IV dose of fludarabine (30-minute infusion); noaccumulation after five daily doses.

References: Hersh MR, et al. Pharmacokinetic study of fludarabine phosphate (NSC 312887). Cancer Chemother Pharmacol, 1986, 17:277–280. PDR54, 2000, p. 764. Plunkett W, et al. Fludarabine: Pharmacokinetics, mechanisms of action, and rationales for combination therapies. Semin Oncol, 1993, 20:2–12.

5-Fluorouracil (5-FU)

28 (0-80)^a

<10

8-12

16 ± 7

0.25 ± 0.12

11 ± 4 min^b

—

11.2 μM^c

^aHigher F with rapid absorption and lower F with slower absorption, due to a saturable first-pass effect. ^bA much longer (~20 hours) terminal t_1/2 has been reported, representing a slow redistribution of drug from tissues. ^cSteady-state concentration following a continuous IV infusion of 300-500 mg/m²/day to cancer patients.

Reference: Diasio RB, et al. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet, 1989, 16:215–237.

Fluoxetine^a

—^a

<2.5

↔ LD, RD

9.6 ± 6.9^b,c

↔ RD, Aged, Obes

↓ LD

35 ± 21^d

↔ RD, LD

53 ± 41^e

↑ LD

↔ RD, Aged, Obes

F: 6-8^f

F: 200-531 ng/mL^f

NF: 103-465 ng/mL^f

^aActive metabolite, norfluoxetine; t_1/2 of norfluoxetine is 6.4 ± 2.5 days (12 ± 2 days in cirrhosis). Absolute bioavailability is unknown, but ≥80% of the dose is absorbed. ^bReduced CL with repetitive dosing (~2.6 mL/min/kg) and with increasing dose between 40 and 80 mg. ^cCL/F reported; fluoxetine is a CYP2D6 substrate and inhibitor. ^dV_area/F reported. ^eLonger t_1/2 with repetitive dosing and with increasing doses. ^fRange of data for fluoxetine (F) andnorfluoxetine (NF) following a 60-mg oral dose given once daily for 1 week. NF continues to accumulate for several weeks.

Reference: Altamura AC, et al. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet, 1994, 26:201–214.

Fluphenazine^a

PO: 2.7 (1.7-4.5)^b

SC or IM: 3.4 (2.5-5.0)^b

Negligible

—

10 ± 7

11 ± 10

IV: 12 ± 4^c

IR: 14.4 ± 7.8^c

SR: 20.3 ± 7.9^c

IR: 2.8 ± 2.1^d

DN: 24-48^d

EN: 48-72^d

IR: 2.3 ± 2.1 ng/mL^d

DN: 1.3 ng/mL^d

EN: 1.1 ng/mL^d

^aData from healthy male and female volunteers. Fluphenazine is extensively metabolized. ^bAvailable in immediate-release (IR) oral and IM formulations and depot SC or IM injections as the enanthate (EN) or decanoate (DN) esters. Geometric mean (90% confidence interval). ^cReported t_1/2 for a single IV dose and apparent t_1/2 following oral administration of IR and slow-release (SR) formulations. Longer apparent t_1/2s with oral dosing reflect an absorption-limited elimination. ^dFollowing a single 12-mg oral dose (IR) or 5-mg IM injections of DN and EN.

References: Jann MW, et al. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet, 1985, 10:315–333. Koytchev R, et al. Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers. Eur J Clin Pharmacol, 1996, 51:183–187.

Flutamide^a

—

F: 94-96

HF: 92-94

280^b

↔ RD

—

F: 7.8^b

HF: 8.1^b

F: 1.3 ± 0.7^c

HF: 1.9 ± 0.6^c

F: 0.11 ± 0.21 μg/mL^c

HF: 1.6 ± 0.59 μg/mL^c

^aData obtained primarily from elderly men. Flutamide (F) is metabolized rapidly to a number of metabolites, which are mainly excreted in urine. One major metabolite, 2-hydroxyflutamide (HF), is biologically active (equal potency); formation is catalyzed primarily by CYP1A2. ^bCL/F and t_1/2 (terminal) reported for oral dose. ^cData for F and HF following a 250-mg oral dose given three times daily to steady state in healthy geriatric male volunteers.

References: Anjum S, et al. Pharmacokinetics of flutamide in patients with renal insufficiency. Br J Clin Pharmacol, 1999, 47:43–47. PDR54, 2000, p. 2798. Radwanski E, et al. Single and multiple dose pharmacokinetic evaluation of flutamide in normal geriatric volunteers. J Clin Pharmacol, 1989, 29:554–558.

Foscarnet

9 ± 2

95 ± 5

14-17

1.6 ± 0.2

↓ RD^a

0.35

5.7 ± 0.2

↑ RD^a

1.4 ± 0.6^b

86 ± 36 μM^b

^aIn patients with moderate to severe renal impairment. ^bFollowing an 8-mg/kg oral dose given once daily for 8 days to HIV-seropositive patients.

References: Aweeka FT, et al. Effect of renal disease and hemodialysis on foscarnet pharmacokinetics and dosing recommendations. J Acquir Immune Defic Syndr Hum Retrovirol, 1999, 20:350–357. Noormohamed FH, et al. Pharmacokinetics and absolute bioavailability of oral foscarnet in human immunodeficiency virus-seropositive patients. Antimicrob Agents Chemother, 1998, 42:293–297.

Fosfomycin^a

28 ± 8 (28-41)

↓ Food^b

82 ± 13

Negligible

2.31 ± 0.22

↓ RD^c

0.36 ± 0.06

2.2 ± 0.5

↑ RD^c

2.0 ± 0.6^d

↑ Food^b

21.8 ± 4.8 μg/mL^d

↓ Food^b

^aFosfomycin is cleared predominantly by renal elimination. Data from adult male subjects. No significant gender differences. Range of mean values from multiple studies shown in parentheses. ^bHigh-fat meal. ^cCL/F reduced in patients with mild to severe renal impairment. ^dFollowing a single 3-g oral dose of fosfomycin trometamol in healthy adults.

References: Bergan T, et al. Pharmacokinetic profile of fosfomycin trometamol. Chemotherapy, 1993, 39:297–301. Cadorniga R, et al. Pharmacokinetic study of fosfomycin and its bioavailability. Chemotherapy, 1977, 23:159–174. Goto M, et al. Fosfomycin kinetics after intravenous and oral administration to human volunteers. Antimicrob Agents Chemother, 1981, 20:393–397. PDR54, 2000, p. 1083.

Fulvestrant^a

—^b

9.3-14.3

3.0-5.3

14-19^c

167^d

8.2 ± 5.2 ng/mL^d

^aEliminated by conjugation (sulfate and glucuronide) and CYP3A4-mediated oxidation. Data reported for men and women; no significant gender differences. ^bFor parenteral administration only. Bioavailability following IM injection has not been reported. ^cElimination t_1/2 following IV administration. The apparent t_1/2 following IM dosing is ~40 days due to very prolonged absorption. ^dFollowing a single 250-mg IM dose given to postmenopausal women with breast cancer.

References: PDR58, 2004, pp. 669–670. Robertson JF, et al. Fulvestrant: Pharmacokinetics and pharmacology. Br J Cancer, 2004, 90(suppl):S7–S10. Robertson JF, et al. Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer. Clin Pharmacokinet, 2004, 43:529–538.

Furosemide^a

71 ± 35 (43-73)

↔ CHF, LD, CRI

71 ± 10 (50-80)

↓ CF

↔ Aged

98.6 ± 0.4 (96-99)

↓ RD, NS, LD, Alb, Aged

↔ CHF, Smk

1.66 ± 0.58 (1.5-3.0)

↓ Aged, RD,^b CHF, Neo, Prem

↔ LD ↑CF

0.13 ± 0.06 (0.09-0.17)

↑ NS, Neo, Prem, LD

↔ RD, CHF, Aged, Smk

1.3 ± 0.8 (0.5-2.0)

↑ Aged, RD,^b CHF, Prem, Neo, LD

↔ NS

1.4 ± 0.8^c

1.7 ± 0.9 μg/mL^c

^aData from healthy adult male subjects. No significant gender differences described. Range of mean values from multiple studies shown in parentheses. ^bCL/F reduced, mild renal impairment. Aged: CL/F reduced with declining renal function. ^cFollowing a single 40-mg oral dose (tablet). Ototoxicity occurs at concentrations >25 μg/mL.

References: Andreasen F, et al. The pharmacokinetics of frusemide are influenced by age. Br J Clin Pharmacol, 1983, 16:391–397. Ponto LL, et al. Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (part I). Clin Pharmacokinet, 1990, 18:381–408. Waller ES, et al. Disposition and absolute bioavailability of furosemide in healthy males. J Pharm Sci, 1982, 71:1105–1108.

Gabapentin

60^a

64-68

1.6 ± 0.3

↓ Aged, RD

0.80 ± 0.09

6.5 ± 1.0

↑ RD

2-3^b

4 μg/mL^b

^aDecreases with increasing dose. Value for 300- to 600-mg dose reported. ^bFollowing an800-mg oral dose given three times daily to steady state in healthy adults. Efficacious atconcentrations >2 μg/mL.

References: Bialer M. Comparative pharmacokinetics of the newer antiepileptic drugs. Clin Pharmacokinet, 1993, 24:441–452. McLean MJ. Gabapentin. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice, 2nd ed. Baltimore, Williams & Wilkins, 1997, pp. 884–898.

Galantamine^a

100 (91-110)

20 (18-22)

5.7 (5.0-6.3)^b

↓ RD,^c LD^c

2.6 (2.4-2.9)

5.7 (5.2-6.3)

2.6 ± 1.0^d

96 ± 29 ng/mL^d

^aPrimarily metabolized by CYP2D6, CYP3A4, and glucuronidation. ^bCYP2D6 poor metabolizers show a lower CL, but dose adjustment is not required. ^cln patients with mild to moderate hepatic or renal insufficiency. ^dFollowing a 12-mg oral dose given twice daily for 7 days in healthy, elderly adults.

References: Bickel U, et al. Pharmacokinetics of galanthamine in humans and corresponding cholinesterase inhibition. Clin Pharmacol Ther, 1991, 50:420–428. Huang F, et al. Pharmacokinetic and safety assessments of galantamine and risperidone after the two drugs are administered alone and together. J Clin Pharmacol, 2002, 42:1341–1351. Scott LJ, et al. Galantamine: A review of its use in Alzheimer's disease. Drugs, 2000, 60:1095–1122.

Ganciclovir

3-5

↑ Food

91 ± 5

1-2

3.4 ± 0.5

↓ RD

1.1 ± 0.2

3.7 ± 0.6

↑ RD

PO: 3.0 ± 0.6^a

IV: 6.6 ± 1.8 μg/mL^a

PO: 1.2 ± 0.4 μg/mL^a

↑ Food

^aFollowing a single 6-mg/kg IV dose (1-hour infusion) or a 1000-mg oral dose given with food three times a day to steady state.

References: Aweeka FT, et al. Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS-related cytomegalovirus retinitis. Clin Pharmacol Ther, 1995, 57:403–412. PDR54, 2000, p. 2624.

Gemcitabine^a

—

<10

Negligible

37.8 ± 19.4^b

↓ Aged

1.4 ± 1.3^c

0.63 ± 0.48^c

↑ Aged

—

26.9 ± 9 μM^d

^aData from patients with leukemia. Rapidly metabolized intracellularly to active di- and triphosphate products; IV administration. ^bWeight-normalized CL is ~25% lower in women, compared to men. ^cV_d and t_1/2 are reported to increase with long duration of IV infusion. ^dSteady-state concentration during a 10-mg/m²/min infusion for 120-640 minutes.

References: Grunewald R, et al. Gemcitabine in leukemia: A phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol, 1992, 10:406–413. PDR54, 2000, p. 1586.

Gemfibrozil

98 ± 1

1.7 ± 0.4

↔ LD, RD

0.14 ± 0.03

1.1 ± 0.2

↔ RD

1-2^a

15-25 μg/mL^a

^aFollowing a 600-mg oral dose given twice daily to steady state.

Reference: Todd PA, et al. Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs, 1988, 36:314–339.

Gentamicin

IM: ~100

>90

<10

CL = 0.82CL_cr + 0.11

↓ Obes

0.31 ± 0.10

↔ RD, Aged, CF, Child

↓ Obes

↑ Neo

2-3^a

IV: 1^b

IM: 0.3-0.75^b

IV: 4.9 ± 0.5 μg/mL^b

IM: 5.0 ± 0.4 μg/mL^b

^aGentamicin has a very long terminal t_1/2 of 53 ± 25 hours (slow release from tissues), which accounts for urinary excretion for up to 3 weeks after a dose. ^bFollowing a single100-mg IV infusion (1 hour) or IM injection given to healthy adults.

References: Matzke GR, et al. Pharmacokinetics of cetirizine in the elderly and patients with renal insufficiency. Ann Allergy, 1987, 59:25–30. Regamey C, et al. Comparative pharmacokinetics of tobramycin and gentamicin. Clin Pharmacol Ther, 1973, 14:396–403.

Glimepiride^a

~100

<0.5

>99.5

0.62 ± 0.26

↑ RD^b

0.18

↑ RD^b

3.4 ± 2.0

↔ RD^b

2-3^c

359 ± 98 ng/mL^c

^aData from healthy male subjects. No significant gender differences. Glimepiride is metabolized by CYP2C9 to an active (approximately one-third potency) metabolite, Ml. ^bCL/F, V_d/F increased and t_1/2 unchanged, moderate to severe renal impairment; presumably mediated through an increase in plasma-free fraction. Ml AUC also increased. ^cFollowing a single 3-mg oral dose.

References: Badian M, et al. Determination of the absolute bioavailability of glimepiride (HOE 490), a new sulphonylurea. Int J Clin Pharmacol Ther Toxicol, 1992, 30:481–482. PDR54, 2000, pp. 1346–1349. Rosenkranz B, et al. Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment. Diabetologia, 1996, 39:1617–1624.

Glipizide

98.4

0.52 ± 0.18^a

↔ RD, Aged

0.17 ± 0.02^a

↔ Aged

3.4 ± 0.7

↔ RD, Aged

2.1 ± 0.9^b

465 ± 139 ng/mL^b

^aCL/F and V_ss/F reported. ^bFollowing a single 5-mg oral dose (immediate-release tablet) given to healthy young adults. An extended-release formulation exhibits a delayed T_max of 6-12 hours.

Reference: Kobayashi KA, et al. Glipizide pharmacokinetics in young and elderly volunteers. Clin Pharm, 1988, 7:224–228.

Glyburide

G: 90-100^a

M: 64-90^a

Negligible

99.8

↓ Aged

1.3 ± 0.5

↓ LD

0.20 ± 0.11

4 ± 1^b

↑ LD, NIDDM

G: ~1.5^c

M: 2-4^c

G: 106 ng/mL^c

M: 104 ng/mL^c

^aData for GLYNASE PRESTAB micronized tablet (G) and MICRONASE tablet (M). ^bt_1/2 for G reported. t_1/2 for M formulation is 6-10 hours, reflecting absorption rate limitation. A long terminal t_1/2 (15 hours), reflecting redistribution from tissues, has been reported. ^cFollowing a3-mg oral GLYNASE tablet taken with breakfast or a 5-mg oral MICRONASE tablet given to healthy adult subjects.

References: Jonsson A, et al. Slow elimination of glyburide in NIDDM subjects. Diabetes Care, 1994, 17:142–145. Drugs@FDA.GLYNASE PRETAB label; http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020051s0161bl.pdf. Accessed July 10, 2010.

Haloperidol^a

60 ± 18

92 ± 2

↑ LD

↔ Aged, Child

11.8 ± 2.9^b

↑ Child, Smk

↓ Aged

18 ± 7

18 ± 5^b

↓ Child

IM: 0.6 ± 0.1^c

PO: 1.7 ± 3.2^c

IM: 22 ± 18 ng/mL^c

PO: 9.2 ± 4.4 ng/mL^c

^aUndergoes reversible metabolism to a less active reduced haloperidol. ^bRepresents net CL of parent drug; reduced haloperidol CL = 10 ± 5 mL · min^–1 · kg^–1 and t_1/2 = 67 ± 51 hours. Slow conversion from reduced haloperidol to parent compound probably responsible for prolonged terminal t_1/2 (70 hours) for haloperidol observed with 7-day sampling. ^cFollowing a single20-mg oral or 10-mg IM dose. Effective concentrations are 4-20 ng/mL.

Reference: Froemming JS, et al. Pharmacokinetics of haloperidol. Clin Pharmacokinet, 1989, 17:396–423.

Heparin

—

Negligible

Extensive

1/(0.65 + 0.008D)

± 0.1^a

↓ Fem

0.058 ± 0.11^b

(26 + 0.323D) ±

12 min^a

↓ Smk

3^c

70 ± 39 ng/mL^c

^aDose (D) is in IU/kg. CL and t_1/2 are dose dependent, perhaps due to saturable metabolism with end-product inhibition. ^bV_area reported. ^cMean of above critical length molecules following a single 5000 IU dose (unfractionated) given by SC injection.

Hydrochlorothiazide

71 ± 15

>95

58 ± 17

4.9 ± 1.1^a

↓ RD, CHF,^b Aged

0.83 ± 0.31^c

↓ Aged

2.5 ± 0.2^d

↑ RD, CHF,^b Aged

SD: 1.9 ± 0.5^e

MD: 2^e

SD: 75 ± 17 ng/mL^e

MD: 91 ± 0.2 ng/mL^e

^aRenal CL reported, which should approximate total plasma CL. ^bChanges may reflect decreased renal function. ^cV_area calculated from individual values of renal CL, terminal t_1/2, and fraction of drug excreted unchanged; 70-kg body weight assumed. ^dLonger terminal t_1/2 of 8 ± 2.8 hours has been reported with a corresponding increase in V_area to 2.8 L/kg. ^eFollowing a single (SD) or multiple (MD) 12.5-mg oral dose of hydrochlorothiazide; MD given once daily for 5 days to healthy adults.

References: Beermann B, et al. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol, 1977, 12:297–303. Jordo L, et al. Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide. Br J Clin Pharmacol, 1979, 7:563–567. O'Grady P, et al. Fosinopril/hydrochlorothiazide: Single dose and steady-state pharmacokinetics and pharmacodynamics. Br J Clin Pharmacol, 1999, 48:375–381.

Hydrocodone^a

—

EM: 10.2 ± 1.8

PM: 18.1 ± 4.5

—

EM: 11.1 ± 3.57^b

PM: 6.54 ± 1.25^b

—

EM: 4.24 ± 0.99^b

PM: 6.16 ± 1.97^b

EM: 0.72 ± 0.46^c

PM: 0.93 ± 0.59^c

EM: 30 ± 9.4 ng/mL^c

PM: 27 ± 5.9 ng/mL^c

^aData from healthy male and female subjects. The metabolism of hydrocodone to hydromorphone (more active) is catalyzed by CYP2D6. Subjects were phenotyped as extensive metabolizers (EM) and poor metabolizers (PM). ^bCL/F and t_1/2 reported for oral dose. ^cFollowing a 10-mg oral dose (syrup). Maximal hydromorphone concentrations are higher in EM than in PM (5.2 versus 1.0 ng/mL).

Reference: Otton SV, et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther, 1993, 54:463–472.

Hydromorphone^a

PO: 42 ± 23

SC: ~80

7.1

14.6 ± 7.6

2.90 ± 1.31^b

2.4 ± 0.6

IV: —^c

PO: 1.1 ± 0.2^c

IV: 242 ng/mL^c

PO: 11.8 ± 2.6 ng/mL^c

^aData from healthy male subjects. Extensively metabolized. The principal metabolite,3-glucuronide, accumulates to much higher (27-fold) levels than the parent drug and may contribute to some side effects (not antinociceptive). ^bV_area reported. ^cFollowing a single2-mg IV (bolus, sample at 3 minutes) or 4-mg oral dose.

References: Hagen N, et al. Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone. J Clin Pharmacol, 1995, 35:37–44. Moulin DE, et al. Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain. Lancet, 1991, 337:465–468. Parab PV, et al. Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos, 1988, 9:187–199.

Hydroxychloroquine^a

79 ± 12

45 ± 3

11.9 ± 5.4^b

525 ± 158

1056 (624-1512)

3.2 (2-4.5)

46 ng/mL (34-79 ng/mL)^c

^aHydroxychloroquine is marketed as a racemic mixture of R- and S-hydroxychloroquine. Data for the racemic mixture is reported. ^bPlasma clearance is reported. Hydroxychloroquine accumulates in red blood cells with an average blood-to-plasma ratio of 7.2. Blood clearance of hydroxychloroquine is 1.3 mL/min/kg. ^cFollowing oral administration of a single 155-mg tablet.

References: Tett SE, et al. A dose-ranging study of the pharmacokinetics of hydroxychloroquine following intravenous administration to healthy volunteers. Br J Clin Pharmacol, 1988, 26:303–313. Tett SE, et al. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol, 1989, 27:771–779.

Hydroxyurea^a

108 ± 18

(79-108)

35.8 ± 14.2

Negligible

72 ± 17 mL/min/m^{2 b}

(36.2-72.3)

19.7 ± 4.6 L/m²

3.4 ± 0.7

(2.8-4.5)

IV: 0.5^c

PO: 1.2 ± 1.2^c

IV: 1007 ± 371 μM^c

PO: 794 ± 241 μM^c

^aData from male and female patients treated for solid tumors. A range of mean values from multiple studies is shown in parentheses. ^bNonrenal elimination of hydroxyurea is thought to exhibit saturable kinetics through a 10- to 80-mg/kg dose range. ^cFollowing a single 2-g,30-minute IV infusion or oral dose.

References: Gwilt PR, et al. Pharmacokinetics and pharmacodynamics of hydroxyurea. Clin Pharmacokinet, 1998, 34:347–358. Rodriguez GI, et al. A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea. Blood, 1998, 91:1533–1541.

Hydroxyzine^a

—

A: 9.8 ± 3.3^b

C: 32 ± 11^b

A: 16 ± 3^b

C: 19 ± 9^b

↑ Aged

A: 20 ± 4^b

C: 7.1 ± 2.3^b,c

↑ Aged, LD

A: 2.1 ± 0.4^d

C: 2.0 ± 0.9^d

A: 72 ± 11 ng/mL^d

C: 47 ± 17 ng/mL^d

^aHydroxyzine is metabolized to an active metabolite, cetirizine. Plasma concentrations of cetirizine exceed those of the parent drug; its t_1/2 is similar to that of hydroxyzine when formed from parent drug. Hydroxyzine data for adults (A) and children (C) are reported. ^bCL/F, V_d/F, and t_1/2 after oral dose reported. ^ct_1/2 increases with increasing age (1-15 years of age). ^dFollowing a single 0.7-mg/kg oral dose given to healthy adults and children.

References: Paton DM, et al. Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin Pharmacokinet, 1985, 10:477–497. Simons FE, et al. Pharmacokinetics and antipruritic effects of hydroxyzine in children with atopic dermatitis. J Pediatr, 1984, 104:123–127. Simons FE, et al. The pharmacokinetics and antihistaminic of the HI receptor antagonist hydroxyzine. J Allergy Clin Immunol, 1984, 73(pt 1):69–75. Simons FE, et al. The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis. J Clin Pharmacol, 1989, 29:809–815. Simons KJ, et al. Pharmacokinetic and pharmacodynamic studies of the H₁-receptor antagonist hydroxyzine in the elderly. Clin Pharmacol Ther, 1989, 45: 9–14.

Ibandronate^a

0.63

54 ± 13

1.8 ± 0.1

↓ RD^b

5.8 ± 1.5

37 ± 5

11 ± 4 ng/mL^c

^aCleared primarily by the kidney. ^bExposure increases 50-100% in patients with moderate and severe renal impairment. ^cFollowing a single 50-mg oral dose.

References: Barrett J, et al. Ibandronate: A clinical pharmacological and pharmacokinetic update. J Clin Pharmacol, 2004, 44:951–965. Bergner R, et al. Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function. J Clin Pharmacol, 2007, 47:942–950.

Ibuprofen^a

>80

>99^b

↔ RA, Alb

0.75 ± 0.20^b,c

↑ CF

↔ Child, RA

0.15 ± 0.02^c

↑ CF

2 ± 0.5^b

↔ RA, CF, Child

↑ LD

1.6 ± 0.3^d

61.1 ± 5.5 μg/mL^d

^aRacemic mixture. Kinetic parameters for the active S-(+)-enantiomer do not differ from those for the inactive R-(–)-enantiomer when administered separately; 63 ± 6% of the R-(–)-enantiomer undergoes inversion to the active isomer. ^bUnbound percent of S-(+)-ibuprofen (0.77 ± 0.20%) is significantly greater than that of R-(–)-ibuprofen (0.45 ± 0.06%). Binding of each enantiomer is concentration dependent and is influenced by the presence of the optical antipode, leading to nonlinear elimination kinetics. ^cCL/F and V_ss/F reported. ^dFollowing a single 800-mg dose of racemate. A level of 10 μg/mL provides antipyresis in febrile children.

References: Lee EJ, et al. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol, 1985, 19:669–674. Lockwood GF, et al. Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships. Clin Pharmacol Ther, 1983, 34:97–103.

Idarubicin^a

I: 28 ± 4

1: 97

IL: 94

29 ± 10

↓ RD^b

24.7 ± 5.9

I: 15.2 ± 3.7

IL: 41 ± 10

IL: ↑ RD^b

I: 5.4 ± 2.4^c

IL: 7.9 ± 2.3^c

I: 6.9 ± 0.1 ng/mL^c

IL: 22 ± 4 ng/mL^c

^aData from male and female patients with cancer. Idarubicin (I) undergoes rapid metabolism to a major active (equipotent) metabolite, idarubicinol (IL). ^bMild to moderate renal impairment. ^cFollowing a single 30- to 35-mg/m² oral dose.

References: Camaggi CM, et al. Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: A crossover study. Cancer Chemother Pharmacol, 1992, 30:307–316. Robert J. Clinical pharmacokinetics of idarubicin. Clin Pharmacokinet, 1993, 24:275–288. Tamassia V, et al. Pharmacokinetic study of intravenous and oral idarubicin in cancer patients. Int J Clin Pharmacol Res, 1987, 7:419–426.

Imatinib^a

98 (87-111)

3.3 ± 1.2

6.2 ± 2.2

22 ± 4

3.3 ± 1.1^b

2.6 ± 0.8 μg/mL^b

^aImatinib is metabolized primarily by CYP3A4. ^bFollowing a 400-mg oral dose given once daily to steady state.

References: Peng B, et al. Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion. J Clin Pharmacol, 2004, 44:158–162. Peng B, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients.J Clin Oncol, 2004, 22:935–942. Product information: Gleevec™ (imatinib mesylate). Basel, Switzerland, Novartis, 2004.

Imipenem/Cilastatin^a

Imipenem

—

69 ± 15

↓ Neo, Inflam

↔ Child, CF

<20

2.9 ± 0.3

↑ Child

↓ RD

↔ CF, Inflam, Neo, Aged, Burn, Prem

0.23 ± 0.05

↑ Neo, Child, Prem

↔ CF, RD, Aged

0.9 ± 0.1

↔ Neo, RD, Prem

↔ CF, Child, Aged

IM: 1-2^b

IV: 60-70 μg/mL^b

IM: 8.2-12 μg/mL^b

Cilastatin

—

70 ± 3

↓ Neo

↔ CF

∼35

3.0 ± 0.3

↑ Child

↓ Neo, RD, Prem

↔ CF, Aged

0.20 ± 0.03

↔ Neo, RD, CF, Aged

↑ Prem

0.8 ± 0.1

↑ Neo, Prem

↔ CF, Aged

^aFormulated as a 1:1 (mg/mg) mixture for parenteral administration; cilastatin inhibits the metabolism of imipenem by the kidney, increasing concentrations of imipenem in the urine; cilastatin does not change imipenem plasma concentrations appreciably. ^bPlasma C_max of imipenem following a single 1-g IV infusion over 30 minutes or 750 mg IM injection.

Reference: Buckley MM, et al. Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs, 1992, 44:408–444.

Indomethacin

∼100

15 ± 8

↔ Alb, Prem, Neo

1.4 ± 0.2

↓ Prem, Neo, Aged

0.29 ± 0.04

↔ Aged

2.4 ± 0.2^a

↔ RA, RD

↑ Neo, Prem, Aged

∼1.3^b

∼2.4 μg/mL^b

^aUndergoes significant enterohepatic recycling (∼50% after an IV dose). ^bFollowing a single50-mg oral dose given after a standard breakfast. Effective at concentrations of 0.3-3 μg/mL and toxic at >5 μg/mL.

Reference: Oberbauer R, et al. Pharmacokinetics of indomethacin in the elderly. Clin Pharmacokinet, 1993, 24:428–434.

Interferon Alfa^a

I-SC: 90

—^b

—

I: 2.8 ± 0.6^c

PI_12kD: 0.17

PI_40kD: 0.014-0.024

I: 0.40 ± 0.19^c

PI_12kD: 0.44-1.04

PI_40kD: 0.11-0.17

I: 0.67^d

PI_12kD: 37(22-60)

PI_40kD: 65

I: 7.3^e

PI_12kD: 22^f

PI_40kD: 80^g

I: 1.7(1.2-2.3) ng/mL^e

PI_12kD: 0.91 ± 0.33 ng/mL^f

PI_40kD: 26 ± 8.8 ng/mL^g

^aValues for recombinant interferon alfa-2a (I) and its 40-kDa pegylated form (PI_40kD) and the 12-kDa pegylated form of interferon alfa-2b (PI_12kD) are reported. ^bI undergoes renal filtration, tubular reabsorption, and proteolytic degradation within tubular epithelial cells. Renal elimination of PI forms is much less significant than that of I, although not negligible. ^cCL values in four patients with leukemia were more than halved (1.1 ± 0.3 mL/min/kg), while V_ss increased more than 20-fold (9.5 ± 3.5 L/kg) and terminal t_1/2 changed only minimally (7.3 ± 2.4 hours). ^dA terminal t_1/2 of 5.1 ± 1.6 hours accounts for 23% of the CL of I. ^eFollowing a single 36 × 10⁶ units SC dose of I. ^fFollowing 4 weeks of multiple SC dosing of 1 μg/kg of PI_12kD. ^gFollowing 48 weekly SC doses of 180 μg of PI_40kD.

References: Glue P, et al. Pegylated interferon-2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther, 2000, 68:556–567. Harris JM, et al. Pegylation: A novel process for modifying pharmacokinetics. Clin Pharmacokinet, 2001, 40:539–551. PDR54, 2000, p. 2654. Wills RJ. Clinical pharmacokinetics of interferons. Clin Pharmacokinet, 1990, 19:390–399.

Interferon Beta

SC: 51 ± 17

—^a

—

13 ± 5^a

2.9 ± 1.8

4.3 ± 2.3

SC: 1-8^b

IV: 1491 ± 659 IU/mL^b

SC: 40 ± 20 IU/mL^b

^aUndergoes renal filtration, tubular reabsorption, and renal catabolism, but hepatic uptake and catabolism are thought to dominate systemic CL. ^bConcentration at 5 minutes following a single 90 × 10⁶ IU IV dose or following a single 90 × 10⁶ IU SC dose of recombinant interferon beta-1b.

Reference: Chiang J, et al. Pharmacokinetics of recombinant human interferon-β_ser in healthy volunteers and its effect on serum neopterin. Pharm Res, 1993, 10:567–572.

Irbesartan^a

60-80

2.2 ± 0.9

2.12 ± 0.54

↓ Aged^b

↔ RD, LD

0.72 ± 0.20

13 ± 6.2

1.2 (0.7-2)^c

1.3 ± 0.4 μg/mL^c

^aData from healthy male subjects. No significant gender differences. Metabolized by UGT and CYP2C9. ^bCL/F reduced; no dose adjustment required. ^cFollowing a single 50-mg oral dose (capsule).

References: Gillis JC, et al. Irbesartan. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension. Drugs, 1997, 54:885–902. PDR54, 2000, p. 818. Vachharajani NN, et al. Oral bioavailability and disposition characteristics of irbesartan, an angiotensin antagonist, in healthy volunteers. J Clin Pharmacol, 1998, 38:702–707.

Irinotecan^a

—

I: 16.7 ± 1.0

I: 30-68

SN-38: 95

I: 14.8 ± 4 L/hr/m²

I: 150 ± 49 L/m²

I: 10.8 ± 0.5

SN-38: 10.4 ± 3.1

I: 0.5^b

SN-38: ≤1^b

I: 1.7 ± 0.8 μg/mL^b

SN-38: 26 ± 12 ng/mL^b

^aData from male and female patients with malignant solid tumors. No significant gender differences. Irinotecan (I) is metabolized to an active metabolite, SN-38 (100-fold more potent but with lower blood levels). ^bFollowing a 125-mg/m² IV infusion over 30 minutes.

References: Chabot GG, et al. Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol, 1995, 6:141–151.

PDR54, 2000, pp. 2412–2413.

Isoniazid^a

—^b

↓ Food

RA: 7 ± 2^c

SA: 29 ± 5^c

∼0

RA: 7.4 ± 2.0^d

SA: 3.7 ± 1.1^d

↔ Aged

↓ RD^e

0.67 ± 0.15^d

↔ Aged, RD

RA: 1.1 ± 0.1

SA: 3.1 ± 1.1

↑ AVH, LD, Neo, RD

↔ Aged, Obes, Child, HTh

RA: 1.1 ± 0.5^f

SA: 1.1 ± 0.6^f

RA: 5.4 ± 2.0 μg/mL^f

SA: 7.1 ± 1.9 μg/mL^f

^aMetabolized by NAT 2 (polymorphic). Data for slow acetylators (SA) and rapid acetylators (RA) reported. ^bIt is usually stated that isoniazid is completely absorbed; however, good estimates of possible loss due to first-pass metabolism are not available. Absorption is decreased by food and antacids. ^cRecovery after oral administration; assay includes unchanged drug and acid-labile hydrazones. Higher percentages have been noted after IV administration, suggesting significant first-pass metabolism. ^dCL/F and V_ss/F reported. ^eDecrease in CL_NR/F as well as CL_R. ^fFollowing a single 400-mg oral dose to healthy RAs and SAs.

Reference: Kim YG, et al. Decreased acetylation of isoniazid in chronic renal failure. Clin Pharmacol Ther, 1993, 54:612–620.

Isosorbide Dinitrate^a

PO: 22 ± 14^b

↔CHF, RD, Smk↑LD

SL: 45 ± 16^b

PC: 33 ± 17^b

28 ± 12

46(38-59)^c

↓ LD

↔ Smk, RD, Fem, CHF

3.1 (2.2-8.6)

0.7 (0.6-2.0)^c

↔ RD, Fem

IR^d

ISDN: 0.3 (0.2-0.5)

IS-2-MN: 0.6 (0.2-1.6)

IS-5-MN: 0.7 (0.3-1.9)

SR^d

ISDN: ∼0

IS-2-MN: 2.8 (2.7-3.7)

IS-5-MN: 5.1 (4.2-6.6)

IR^d

ISDN: 42 (59-166) nM

IS-2-MN: 207 (197-335) nM

IS-5-MN: 900 (790-1080) nM

SR^d

ISDN: ∼0

IS-2-MN: 28 (23-33) nM

IS-5-MN: 175 (154-267) nM

^aIsosorbide dinitrate (ISDN) is metabolized to the 2- and 5-mononitrates (IS-2-MN and IS-5-MN). Both metabolites and the parent compound are thought to be active. Data for the dinitrate are reported except where indicated. ^bBioavailability calculations from single dose. SL, sublingual; PC, percutaneous. ^cCL may be decreased and t_1/2 prolonged after chronic dosing. ^dMean (range) for ISDN and IS-2-MN and IS-5-MN following a single 20-mg oral immediate-release (IR) and sustained-release (SR) dose.

References: Abshagen U, et al. Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration. Eur J Clin Pharmacol, 1985, 27:637–644. Fung HL. Pharmacokinetics and pharmacodynamics of organic nitrates. Am J Cardiol, 1987, 60:4H–9H.

Isosorbide 5-Mononitrate (Isosorbide Nitrate)^a

93 ± 13

↔ LD, RD, Aged, CAD

1.80 ± 0.24

↔ LD, RD, Aged, CAD

0.73 ± 0.09

↔ LD, RD, MI, Aged, CAD

4.9 ± 0.8

↔ LD, RD, MI, Aged, CAD

1-1.5^b

314-2093 nM^b

^aActive metabolite of isosorbide dinitrate. ^bFollowing a 20-mg oral dose given by asymmetric dosing (0 and 7 hours) for 4 days.

Reference: Abshagen UW. Pharmacokinetics of isosorbide mononitrate. Am J Cardiol, 1992, 70:61G–66G.

Isotretinoin^a

40^b

↑ Food

Negligible

>99

5.5 (0.9-11.1)^c

5 (1-32)^c

17 (5-167)^d

I: 4.5 ± 3.4^e

4-oxo: 6.8 ± 6.5^e

I: 208 ± 92 ng/mL^e

4-oxo: 473 ± 171 ng/mL^e

^aIsotretinoin (I) is eliminated through metabolic oxidations catalyzed by multiple CYPs (2C8, 2C9, 3A4, and 2B6). The 4-oxo-isotretinoin metabolite (4-oxo) is active and found at higher concentrations than parent drug at steady state. ^bBioavailability when taken with food is reported. ^cCL/F and V/F reported. ^d4-oxo has an apparent mean t_1/2 of 29 ± 6 hours. ^eValues for I and 4-oxo following a 30-mg oral dose given once daily to steady state.

References: Larsen FG, et al. Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases. Clin Pharmacokinet, 1992, 23:42–61. Nulman I, et al. Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: Implications for fetal safety. J Clin Pharmacol, 1998, 38:926–930. Wiegand UW, et al. Pharmacokinetics of oral isotretinoin. J Am Acad Dermatol, 1998, 39:S8–S12.

Itraconazole^a

↑ Food

↓ HIV^b

99.8

5.1^c

10.7^d

21 ± 6^e

3-5^f

649 ± 289 ng/mL^f

↑ Food

^aMetabolized predominantly by CYP3A4 to an active metabolite, hydroxyitraconazole, and other sequential metabolites. ^bRelative to oral dosing with food. ^cBlood CL is 9.4 mL/min/kg. CL is concentration dependent; the value given is nonsaturable range. K_m = 330 ± 200 ng/mL, V_max = 2.2 ± 0.8 pg · mL⁻¹ · min⁻¹ · kg⁻¹. Apparent CL/F at steady state reported to be 5.4 mL · min⁻¹ · kg⁻¹· ^dV_area reported. Follows multicompartment kinetics. Does not appear to be concentration dependent. ^et_1/2 for the nonsaturable concentration range. t_1/2 at steady state reported to be 64 hours. ^fFollowing a 200-mg oral dose given daily for 4 days to adults.

References: Heykants J, et al. The pharmacokinetics of itraconazole in animals and man. An overview. In: Fromtling RA, ed. Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona, Prous Science Publisher, 1987, pp. 223–249. Jalava KM, et al. Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther, 1997, 61:410–415.

Ivermectin^a

—

93.1 ± 0.2

2.06 ± 0.81^b

9.91 ± 2.67^b

56.5 ± 7.5^b

4.7 ± 0.5^c

38.2 ± 5.8 ng/mL^c

^aData from male and female patients treated for onchocerciasis. Metabolized by hepatic enzymes and excreted into bile. ^bCL/F, V_area/F, and t_1/2 reported for oral dose. Terminalt_1/2 reported. ^cFollowing a single 150-μg/kg oral dose (tablet).

References: Okonkwo PO, et al. Protein binding and ivermectin estimations in patients with onchocerciasis. Clin Pharmacol Ther, 1993, 53:426–430. PDR54, 2000, p. 1886.

Ketorolac^a

100 ± 20

5-10

99.2 ± 0.1

0.50 ± 0.15

↓ Aged, RD^b

↔ LD

0.21 ± 0.04

5.3 ± 1.2

↑ Aged, RD^b

↔ LD

IM: 0.7-0.8^c

PO: 0.3-0.9^c

IM: 2.2-3.0 μg/mL^c

PO: 0.8-0.9 μg/mL^c

^aRacemic mixture; S-(–)-enantiomer is much more active than the R-(+)-enantiomer. Following IM injection, the mean AUC ratio for S/R-enantiomers was 0.44 ± 0.04, indicating a higher CL and shorter t_1/2 for the S-(–)-enantiomer. Values reported are for the racemate. ^bProbably due to the accumulation of glucuronide metabolite, which is hydrolyzed back to parent drug. ^cRange of mean C_max and T_max from different studies following a single 30-mg IM or 10-mg oral dose in healthy adults. Reference: Brocks DR, et al. Clinical pharmacokinetics of ketorolac tromethamine. Clin Pharmacokinet, 1992, 23:415–427.

Lamotrigine^a

97.6 ± 4.8

0.38-0.61^b,c

↓ LD,^d RD^e

0.87-1.2

24-35^c

↑ LD,^d RD^e

2.2 ± 1.2^f

2.5 ± 0.4 μg/mL^f

^aLamotrigine is eliminated primarily by glucuronidation. The parent-metabolite pair may undergo enterohepatic recycling. Data from healthy adults and patients with epilepsy. Range of mean values from multiple studies reported. ^bCL/F increases slightly with multiple-dose therapy. ^cCL/F increased and t_1/2 decreased in patients receiving enzyme-inducing anticonvulsant drugs. ^dCL/F reduced, moderate to severe hepatic impairment. ^eCL/F reduced, severe RD. ^fFollowing a single 200-mg oral dose to healthy adults.

References: Chen C, et al. Pharmacokinetics of lamotrigine in children in the absence of other antiepileptic drugs. Pharmacotherapy, 1999, 19:437–441. Garnett WR. Lamotrigine: Pharmacokinetics. J Child Neurol, 1997, 12(suppl 1):S10–S15. PDR54, 2000, p. 1209. Wootton R, et al. Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers. Br J Clin Pharmacol, 1997, 43:23–27.

Leflunomide^a

—^b

Negligible

99.4

↓ RD

0.012^c

↑ RD

0.18 (0.09-0.44)^c

↑ RD

377 (336-432)^d

↔ RD

6-12^e

35 μg/mL^e

^aLeflunomide is a prodrug that is converted almost completely (∼95%) to an active metabolite A77–1726 (2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-crotonamide). All pharmacokinetic data reported are for the active metabolite. ^bAbsolute bioavailability is not known; parent drug/metabolite are well absorbed. ^cApparent CL/F and V/F in healthy volunteers reported. Both parameters are a function of the bioavailability of leflunomide and the extent of its conversion to A77–1726. ^dIn patients with RA. ^eFollowing a 20-mg oral dose given once daily to steady state in patients with RA.

Reference: Rozman B. Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet, 2002, 41:421–430.

Lenalidomide^a

>80^b

84^c

35 ± 4

↔ RD^d

2.8^e

↓ RD^d

0.8^e

3.3

↑ RD^d

1 (0.5-2.0)

568 ± 221 ng/mL^f

^aLenalidomide is administered as a racemic mixture. Data for the racemate is shown. ^bBased on urine recovery of unchanged drug after oral administration. Lenalidomide is primarily eliminated via urinary excretion. ^cPercentage of oral dose recovered unchanged in urine. ^dStudy in patients with mild, moderate, severe, and end-stage renal impairment; exposure increases 150% in moderate renal impairment and 375% in severe renal impairment. ^eCL/F and V/F reported. ^fFollowing a single 25-mg oral dose.

Reference: Chen N, et al. Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J Clin Pharmacol, 2007, 47:1466–1475.

Letrozole^a

99.9 ± 16.3

3.9 ± 1.4

0.58 ± 0.21

↓ LD^b

1.87 ± 0.46

45 ± 16

1.0^c

115 nM^c

^aData from healthy postmenopausal female subjects. Metabolized by CYP3A4 and CYP2A6. ^bCL/F reduced, severe hepatic impairment. ^cFollowing a single 2.5-mg oral dose (tablet).

References: Lamb HM, et al. Letrozole. A review of its use in postmenopausal women with advanced breast cancer. Drugs, 1998, 56:1125–1140. Sioufi A, et al. Absolute bioavailability of letrozole in healthy postmenopausal women. Biopharm Drug Dispos, 1997, 18:779–789.

Levetiracetam^a

∼100

<10

0.96

↓ RD,^b Aged, LD^c

↑ Child^d

0.5-0.7

7 ± 1

↑ RD,^b Aged

0.5-1.0^e

∼10 μg/mL^e

^aData from healthy adults and patients with epilepsy. No significant gender differences. ^bCL/F reduced, mild renal impairment (cleared by hemodialysis). ^cCL/F reduced, severe hepatic impairment. ^dCL/F increased, 6-12 years of age. ^eFollowing a single 500-mg dose given to healthy adults.

Reference: Physicians' Desk Reference, 55th ed. Montvale, NJ, Medical Economics Co., 2001, pp. 3206–3207.

Levodopa^a

41 ± 16

↑ Aged

86 ± 19^b

↔ Aged

—

23 ± 4

↓ Aged

9 ± l^b

↓ Aged

1.7 ± 0.4

↓ Aged

0.9 ± 0.2^b

↓ Aged

1.4 ± 0.4

↔ Aged

1.5 ± 0.3^b

↔ Aged

Y: 1.4 ± 0.7^c

E: 1.4 ± 0.7^c

Y: 1.7 ± 0.8 μg/mL^c

E: 1.9 ± 0.6 μg/mL^c

^aNaturally occurring precursor to dopamine. ^bValues obtained with concomitant carbidopa (inhibitor of dopa decarboxylase). ^cFollowing a single 125-mg oral dose of levodopa given with carbidopa (100 mg 1 hour before and 50 mg 6 hours after levodopa) in young (Y) and elderly (E) subjects.

Reference: Robertson DR, et al. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol, 1989, 28:61–69.

Levofloxacin^a

99 ± 10

61-87

24-38

2.52 ± 0.45

↓ RD^b

1.36 ± 0.21

7 ± 1

↑ RD^b

1.6 ± 0.8^c

4.5 ± 0.9 μg/mL^c

^aData from healthy adult male subjects. Gender and age differences related to renal function. ^bCL/F reduced, mild to severe renal impairment (not cleared by hemodialysis). ^cFollowing a single 500-mg oral dose. No significant accumulation with once-daily dosing.

References: Chien SC, et al. Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses. Antimicrob Agents Chemother, 1997, 41:2256–2260. Fish DN, et al. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet, 1997, 32:101–119. PDR54, 2000, p. 2157.

Linezolid

100

2.1 ± 0.8

↑ Child

0.57-0.71

5.2 ± 1.7

↓ Child

PO: 1.4 ± 0.5^a

PO: 16 ± 4 μg/mL^a

IV: 15 ± 3 μg/mL^b

^aFollowing a 600-mg oral dose given twice daily to steady state. ^bFollowing a 30-minute IV infusion of a 600-mg dose given twice daily to steady state in patients with gram-positive infection.

References: MacGowan AP. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother, 2003, 51(suppl 2):ii17–ii25. Stalker DJ, et al. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet, 2003, 42:1129–1140.

Lisinopril

25 ± 20

↓ CHF

88-100

4.2 ± 2.2^a

↓ CHF, RD, Aged

↔ Fem

2.4 ± 1.4^a

↔ Aged, RD

12^b

↑ Aged, RD

∼7^c

50 (6.4-343) ng/mL^c

^aCL/F and V_area/F reported. ^bEffective t_1/2 to predict steady-state accumulation upon multiple dosing; a terminal t_1/2 of 30 hours reported. ^cFollowing a 2.5- to 40-mg oral dose given daily to steady state in elderly patients with hypertension and varying degrees of renal function. EC₉₀ for ACE inhibition is 27 ± 10 ng/mL.

Reference: Thomson AH, et al. Lisinopril population pharmacokinetics in elderly and renal disease patients with hypertension. Br J Clin Pharmacol, 1989, 27:57–65.

Lithium

100^a

95 ± 15

0.35 ± 0.11^b

↓ RD, Aged

↑ Preg

↔ Obes

0.66 ± 0.16

↓ Obes

22 ± 8^c

↑ RD, Aged

↓ Obes

IR: 0.5-3^d

SR: 2-6^d

IR: 1-2 mM^d

SR:0.7-1.2 mM^d

^aValues as low as 80% reported for some prolonged-release preparations. ^bRenal CL of Li⁺ parallels that of Na⁺. The ratio of Li⁺ and creatinine CL is ∼0.2 ± 0.03. ^cThe distribution t_1/2 is 5.6 ± 0.5 hours; this influences drug concentrations for at least 12 hours. ^dFollowing a single 0.7-mmol/kg oral dose of immediate-release (IR) lithium carbonate and sustained-release (SR) tablets.

Reference: Ward ME, et al. Clinical pharmacokinetics of lithium. J Clin Pharmacol, 1994, 34:280–285.

Lopinavir^a

—^b

↑ Food

98-99

1.2^c

0.6^c

5.3 ± 2.5

4.4 ± 2.4^d

9.8 ± 3.7 μg/mL^d

^aCurrently formulated in combination with ritonavir (KALETRA). Ritonavir inhibits the CYP3A-dependent metabolism of lopinavir, enhancing its bioavailability, increasing plasma concentrations (50- to 100-fold), and extending its t_1/2. Pharmacokinetic data from male and female patients with HIV are reported. ^bAbsolute bioavailability is not known; the relative bioavailability increases with a high-fat meal. ^cCL/F and V_area/F reported; calculated from steady-state AUC data. ^dFollowing a 400/100-mg lopinavir/ritonavir oral dose given twice daily in combination with stavudine and lamivudine to steady state.

References: Boffito M, et al. Lopinavir protein binding in vivo through the 12-hour dosing interval. Ther Drug Monit, 2004, 26:35–39. Corbett AH, et al. Kaletra (lopinavir/ritonavir). Ann Pharmacother, 2002, 36:1193–1203. Eron JJ, et al. Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: A 48-week randomized clinical trial. J Infect Dis, 2004, 189:265–272. King JR, et al. Pharmacokinetic enhancement of protease inhibitor therapy. Clin Pharmacokinet, 2004, 43:291–310.

Loratadine^a

L: —^b

L: Negligible

L: 97

L: 142 ± 57^d

↔ RD

↓ LD

L: 120 ± 80^d

↔ RD

L: 8 ± 6

↔ RD

↑ LD

L (L): 2.0 ± 2.0^e

DL (L): 2.6 ± 2.9^e

L (L): 3.4 ± 3.4 ng/mL^e

DL (L):4.1 ± 2.6 ng/mL^e

DL: —^b

DL: —

DL: 82-87^c

DL: 14-18^d

↓ RD, LD

DL: 26^d

DL: 21-24

DL (DL): 3.2 ± 1.8^f

HDL (DL): 4.8 ± 1.9^f

DL(DL): 4.0 ± 2.1 ng/mL^f

HDL (DL): 2.0 ± 0.6 ng/mL^f

^aLoratadine (L) is converted to a major active metabolite, desloratadine (DL). Almost all patients achieve higher plasma concentrations of DL than of L. DL (CLARINEX) is approved for similar clinical indications as L. DL is eliminated by metabolism. DL is eliminated by metabolism to an active metabolite, 3-hydroxydesloratidine (HDL). ∼7-20% of patients are slow metabolizers of DL; frequency varies with ethnicity. ^bBioavailability of L and DL is not known; L is probably low due to extensive first-pass metabolism. ^cPlasma protein binding of HDL is 85-89%. ^dCL/F and V_area/F reported. For DL, oral CL/F calculated from AUC data following a single 5- to 20-mg oral dose given to healthy adults. ^eMean for L and DL following a 10-mg oral L dose (CLARITIN-D 24 HOUR) given once daily for 7 days to healthy adults. ^fMean for DL and HDL following a 5-mg oral DL dose (CLARINEX) given once daily for 10 days to healthy adults.

References: Affrime M, et al. A pharmacokinetic profile of desloratadine in healthy adults, including elderly. Clin Pharmacokinet, 2002, 41(suppl):13–19. Gupta S, et al. Desloratadine demonstrates dose proportionality in healthy adults after single doses. Clin Pharmacokinet, 2002, 41(suppl):l–6. Haria M, et al. Loratadine. A reappraisal of its pharmacological properties and therapeutic use in allergic disorders. Drugs, 1994, 48:617–637. Kosoglou T, et al. Pharmacokinetics of loratadine and pseudoephedrine following single and multiple doses of once- versus twice-daily combination tablet formulations in healthy adult males. Clin Ther, 1997, 19:1002–1012. PDR58, 2004, p. 3044.

Lorazepam

93 ± 10

91 ± 2

↓ LD, RD

↔ Aged, Burn

1.1 ± 0.4^a

↔ Aged, Cirr, AVH, Smk, RD

↑ Burn, CF

1.3 ± 0.2^b

↑ LD, Burn, CF, RD

↔ Aged, AVH

14 ± 5

↑ LD, Neo, RD

↔ Aged, CPBS, AVH

↓ Burn

IM: 1.2^c

PO: 1.2-2.6^c

IV: ∼75 ng/mL^c

IM: ∼30 ng/mL^c

PO: ∼28 ng/mL^c

^aEliminated primarily by glucuronidation. ^bV_area reported. ^cFollowing a single 2-mg IV bolus dose, IM dose, or oral dose given to healthy adults.

Reference: Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet, 1981, 6:89–105.

Losartan^a

L: 35.8 ± 15.5

L: 12 ± 2.8

L: 98.7

LA: 99.8

L: 8.1 ± 1.8

↓ RD,^b LD^c

L: 0.45 ± 0.24

L: 2.5 ± 1.0

LA: 5.4 ± 2.3

L: 1.0 ± 0.5^d

LA: 4.1 ± 1.6^d

L: 296 ± 217 ng/mL^d

LA: 249 ± 74 ng/mL^d

^aData from healthy male subjects. Losartan (L) is metabolized primarily by CYP2C9 to an active 5-carboxylic acid metabolite (LA). ^bCL/F for L but not LA decreased in severe renal impairment (L/LA not removed by hemodialysis). No dose adjustment required. ^cCL/F for L reduced in mild to moderate hepatic impairment. LA AUC also increased. ^dFollowing a single 50-mg oral dose (tablet). Higher plasma levels of L (but not LA) in female subjects than in male subjects.

References: Lo MW, et al. Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans. Clin Pharmacol Ther, 1995, 58:641–649. PDR54, 2000, pp. 1809–1812.

Lovastatin^a

≤5

↑ Food

>95

4.3-18.3^b

↓ RD

—

1-4

AI: 2.0 ± 0.9^c

TI: 3.1 ± 2.9^c

AI: 41 ± 6 ng-Eq/mL^c

TI: 50 ± 8 ng-Eq/mL^c

^aLovastatin is an inactive lactone that is metabolized to the corresponding active β-hydroxy acid. Pharmacokinetic values are based on the sum of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibition activity by the β-hydroxy acid and other less potent metabolites. ^bThe lactone (in equilibrium with β-hydroxy acid metabolite) is metabolized by CYP3A. ^cFollowing an 80-mg oral dose given once daily for 17 days. Peak levels represent total active inhibitors (AI) and total inhibitors (TI) of HMG-CoA reductase.

References: Corsini A, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther, 1999, 84:413–428. Desager JP, et al. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet, 1996, 31:348–371. McKenney JM. Lovastatin: A new cholesterol-lowering agent. Clin Pharm, 1988, 7:21–36.

Maraviroc^a

23-33

8.3^b

10.5 ± 1.3

2.8 ± 0.9

13.2 ± 2.8

3.1 (0.5-4.0)

1177 (895-1459) ng/mL^c

^aCleared primarily by metabolism, with CYP3A4 being the major cytochrome P450 enzyme mediating the N-dealkylation of maraviroc. ^bThe fraction of dose excreted unchanged increases from 1.5-12% with increasing doses (1- to 1200-mg single oral doses). ^cFollowing a 600-mg oral dose once daily for 7 days.

References: Abel S, et al. Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects. Br J Clin Pharmacol, 2008, 65(suppl 1):60–67. Abel S, et al. Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers. Br J Clin Pharmacol, 2008, 65(suppl 1):5–18. Hyland R, et al. Maraviroc: In vitro assessment of drug-drug interaction potential. Br J Clin Pharmacol, 2008, 66:498–507.

Mefloquine^a

—^b

98.2

0.43 ± 0.14^c

↑ Preg

↔ Child

19 ± 6^c

20 ± 4 days

↓ Preg

↔ Child

SD: 7-19.6^d

MD: 12 ± 8^d

SD: 800-1020 ng/mL^d

MD: 420 ±

141 ng/mL^d

^aRacemic mixture; no information on relative kinetics of the enantiomers. ^bAbsolute bioavailability is not known; reported values of >85% represent comparison of oral tablet to solution. ^cCL/F and V_ss/F reported. ^dRange of mean values from different studies following a single 1000-mg oral dose (SD) and mean following a 250-mg oral dose given once weekly for4 weeks (MD).

Reference: Karbwang J, et al. Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet, 1990, 19:264–279.

Memantine^a

~100

48^b

2.1 ± 0.4^c

↓ RD^d

10.9^e

64 ± 10

↑ RD^f

7.6 ± 3.7

22 ± 5 ng/mL^g

^aCleared primarily by the kidney and to a lesser extent by non-cytochrome P450-dependent metabolism. ^bAfter a 20-mg single oral dose. ^cCL/F reported. ^dStudy in patients with moderate to severe renal impairment. ^eV_β/F reported. ^fStudy in patients with severe renal impairment. ^gFollowing a single 20-mg oral dose.

References: Periclou A, et al. Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther, 2006, 79:134–143. Periclou AP, et al. Lack ofpharmacokinetic or pharmacodynamic interaction between memantine and donepezil.Ann Pharmacother, 2004, 38:1389–1394.

Meperidine^a

52 ± 3

↑ LD

~5 (l-25)^b

58 ± 9^c

↓ Aged, RD

↔ LD

17 ± 5

↓ AVH, LD, RD, Prem, Neo

↔ Aged, Preg, Smk

4.4 ± 0.9

↑ Aged, Prem

↔ LD, Preg, RD

3.2 ± 0.8^d

↑ AVH, LD, Prem, Neo, Aged, RD

↔ Preg

IM: <l^e

IV: 0.67 μg/mL^e

IM: ~0.7 μg/mL^e

^aMeperidine undergoes cytochrome P450-dependent N-demethylation to normeperidine. The metabolite is not an analgesic but is a potent central nervous system–excitatory agent and is associated with adverse side effects of meperidine. ^bMeperidine is a weak base (pK_a = 8.6) and is excreted to a greater extent in the urine at low urinary pH and to a lesser extent at high urinary pH. ^cCorrelates with the concentration of α₁-acid glycoprotein. ^dA longer t_1/2 (7 hours) also is observed. ^eFollowing a continuous 24-mg/hr IV infusion or 100-mg IM injection every4 hours to steady state. Postoperative analgesia occurs at 0.4-0.7 μg/mL.

Reference: Edwards DJ, et al. Clinical pharmacokinetics of pethidine: 1982. Clin Pharmacokinet, 1982, 7:421–433.

Mercaptopurine^a

12 ± 7^b

22 ± 12

11 ± 4^c

0.56 ± 0.38

0.90 ± 0.37

PO (−): 2.4 ± 0.4^d

PO (+): 2.8 ± 0.4^d

IV: 6.9 μM^d

PO (−): 0.74 ± 0.28 μM^d

PO (+): 3.7 ± 0.6 μM^d

^aInactive prodrug is metabolized intracellularly to 6-thioinosinate. Pharmacokinetic values for mercaptopurine are reported. ^bIncreases to 60% when first-pass metabolism is inhibited by allopurinol (100 mg three times daily). ^cMetabolically cleared by xanthine oxidase and thiopurine methyltransferase (polymorphic). Despite inhibition of intrinsic CL by allopurinol, hepatic metabolism is limited by blood flow, and CL is thus little changed by allopurinol. ^dFollowing an IV infusion of 50 mg/m²/hr to steady state in children with refractory cancers or a single oral dose of 75 mg/m² with (+) or without (−) allopurinol pretreatment.

References: Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol, 1992, 43:329–339. PDR54, 2000, p. 1255.

Metformin^a

52 ± 5

(40-55)

99.9 ± 0.5

(79-100)

Negligible

7.62 ± 0.30

(6.3-10.1)

↓ RD,^b Aged

1.12 ± 0.08

(0.9-3.94)

1.74 ± 0.20

(1.5-4.5)

↑ RD,^b Aged

1.9 ± 0.4^c

(1.5-3.5)^c

1.6 ± 0.2 μg/mL^c

(1.0-3.1 μg/mL)^c

^aData from healthy male and female subjects. No significant gender differences. Shown in parentheses are mean values from different studies. ^bCL/F reduced, mild to severe renal impairment. ^cFollowing a single 0.5-g oral dose (tablet) and range for a 0.5- to 1.5-g oral dose.

References: Harrower AD. Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency. Clin Pharmacokinet, 1996, 37:111–119. Pentikainen PJ, et al. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol, 1979, 16:195–202. PDR54, 2000, pp. 831–835. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet, 1996, 30:359–371.

Methadone^a

92 ± 21

24 ± 10^b

89 ± 2.9^c

1.7 ± 0.9^b

↓ Burn, Child

3.6 ± 1.2^d

27 ± 12^e

↓ Burn, Child

~3^f

IV: 450-550 ng/mL^f

PO: 69-980 ng/mL^f

^aData for racemic mixture. Opioid activity resides with the R-enantiomer. In vivo disposition is stereoselective. N-demethylation is mediated by CYP3A4 and CYP2B6. ^bInversely correlated with urine pH. ^cd-methadone slightly higher percent bound. ^dV_area reported. Directly correlated with urine pH. ^eDirectly correlated with urine pH. ^fFollowing a single 10-mg IV bolus dose in patients with chronic pain or a 0.12- to 1.9-mg/kg oral dose once daily for at least2 months in subjects with opioid dependency. Levels >100 ng/mL prevent withdrawal symptoms; EC₅₀ for pain relief and sedation in cancer patients is 350 ± 180 ng/mL.

References: Dyer KR, et al. Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: Comparison of those who do and do not experience withdrawal and concentration-effect relationships. Clin Pharmacol Ther, 1999, 65:685–694. Inturrisi CE, et al. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther, 1987, 41:392–401.

Methotrexate^a

70 ± 27^b,c

81 ± 9

46 ± 11

2.1 ± 0.8

↓ RD

↔ RA

0.55 ± 0.19

7.2 ± 2.1^d

↔ RA

SC: 0.9 ± 0.2^e

SC: 1.1 ± 0.2 μM^e

IV: 37-99 μM^e

^aPlasma concentrations of the 7-hydroxy metabolite approach those of the parent drug. Metabolite may have both therapeutic and toxic effects. ^bBioavailability is dose dependent and may be as low as 20% when doses are >80 mg/m². ^cIM bioavailability is only slightly higher. ^dExhibits triexponential elimination kinetics. A shorter t_1/2 (2 hours) is seen initially, and a longer (52 hours) terminal t_1/2 has been observed with increased assay sensitivity. ^eFollowing a 15-mg SC dose given once weekly to steady state in adult patients with inflammatory bowel disease. Initial steady-state concentrations in young (1.5-22 years of age) leukemia patients receiving a 500-mg/m² loading dose given over 1 hour followed by an infusion of 196 mg/m²/hr for 5 hours.

References: Egan LJ, et al. Systemic and intestinal pharmacokinetics of methotrexate in patients with inflammatory bowel disease. Clin Pharmacol Ther, 1999, 65:29–39. Tracy TS, et al. Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol, 1994, 37:453–456. Wall AM, et al. Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia. Leukemia, 2000, 14:221–225.

Methylphenidate^a

(+): 22 ± 8

(−): 5 ± 3

(+): 1.3 ± 0.5

(−): 0.6 ± 0.3

(+/−): 15-16

(+): 6.7 ± 2.0^b

(−): 12 ± 4.7^b

(+): 2.7 ± 1.1

(−): 1.8 ± 0.9

(+): 6.0 ± 1.7^c

(−): 3.6 ± 1.1

(+): 2.4 ± 0.8^c,d

(−): 2.1 ± 0.6^d

(+): 18 ± 4.3 ng/mL^d

(−): 3.0 ± 0.9 ng/mL^d

^aMethylphenidate is available as a racemate and the active (+)-dextro-enantiomer, dexmethylphenidate. Methylphenidate and dexmethylphenidate are extensively metabolized, primarily through ester hydrolysis to ritalinic acid. Data for individual enantiomers following racemate administration to healthy adult male subjects. No significant gender differences. ^bThe (+)-enantiomer exhibits dose-dependent kinetics at high doses of racemate, with a ~50% reduction in CL/F between a 10- to 40-mg dose. ^cWhen dexmethylphenidate is given alone, its t_1/2 is 2.2 hours, and T_max is 1-1.5 hours. ^dFollowing a single 40-mg oral dose (immediate release). Longer T_max (3-5 hours) and lower C_max reported for sustained-released oral formulation.

References: Aoyama T, et al. Nonlinear kinetics of threo-methylphenidate enantiomers in a patient with narcolepsy and in healthy volunteers. Eur J Clin Pharmacol, 1993, 44:79–84. Keating GM, et al. Dexmethylphenidate. Drugs, 2002, 62:1899–1904; discussion 1905–1908. Kimko HC, et al. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet, 1999, 37:457–470. PDR58, 2004, pp. 2265, 2297–2298. Srinivas NR, et al. Enantioselective pharmacokinetics of dl-threo-methyl-phenidate in humans. Pharm Res, 1993, 10:14–21.

Methylprednisolone

82 ± 13^a

4.9 ± 2.3

↔ LD

78 ± 3

↔ Fem

↓ LD

6.2 ± 0.9

↔ NS, RA, CRI, LD

↓ Obes

↑ Fem

1.2 ± 0.2

↔ NS, RD, RA, CRI, LD

↓ Obes, Fem

2.3 ± 0.5

↔ NS, RD, RA, CRI, LD

↑ Obes

↓ Fem

PO: 1.64 ± 0.64^c

IV: 225 ± 44 ng/mL^b

PO: 178 ± 44 ng/mL^c

^aMay be decreased to 50-60% with high doses. ^bMean at 1 hour following a 28-mg IV infusion over 20 minutes given twice daily for 6 ± 4 days during the perioperative period following kidney transplantation. ^cMean data following a 24-mg oral dose given twice daily for3 days in healthy adult male subjects.

References: Lew KH, et al. Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther, 1993, 54:402–414. Rohatagi S, et al. Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration. J Clin Pharmacol, 1997, 37:916–925. Tornatore KM, et al. Methylprednisolone and cortisol metabolism during the early post-renal transplant period. Clin Transplant, 1995, 9:427–432.

Metoclopramide

76 ± 38

↔ Aged, LD

20 ± 9

40 ± 4

↔ RD

6.2 ± 1.3

↓ RD, LD

↓ Neo

↔ Aged

3.4 ± 1.3

↔ RD, LD, Aged

↓ Neo

5.0 ± 1.4

↑ RD, LD

↔ Aged

A: ≤1^a

I: 2.5 ± 0.7^a

A: 80 ng/mL^a

I: 18 ± 6.2 ng/mL^a

^aFollowing a single 20-mg oral dose given to healthy adults (A) or an oral (nasogastric) dose of 0.10-0.15 mg/kg given four times daily to steady state to premature infants (I), 1-7 weeks of age (26-36 weeks, postconceptional).

References: Kearns GL, et al. Pharmacokinetics of metoclopramide in neonates. J Clin Pharmacol, 1998, 38:122–128. Lauritsen K, et al. Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (part I). Clin Pharmacokinet, 1990, 19:11–31. Rotmensch HH, et al. Comparative central nervous system effects and pharmacokinetics of neu-metoclopramide and metoclopramide in healthy volunteers. J Clin Pharmacol, 1997, 37:222–228.

Metoprolol^a

38 ± 14^b

↑ LD

↓ Preg

10 ± 3^b

11 ± 1

↔ Preg

15 ± 3^b

↑ HTh, Preg

↔ Aged, Smk

↑ Fem

4.2 ± 0.7

↑ Fem

3.2 ± 0.2^b

↑ LD, Neo

↔ Aged, HTh, Preg, Smk

EM: ~2^c

PM: ~3^c

EM: 99 ± 53 ng/mL^c

PM: 262 ± 29 ng/mL^c

^aData for racemic mixture reported. Metabolism of less active R-(+)-enantiomer (CL/F =28 mL/min/kg; V_area/F = 7.6 L/kg; t_1/2 = 2.7 hours) is slightly faster than that of more activeS-(−)-enantiomer (CL/F = 20 mL/min/kg; V_area/F = 5.5 L/kg; t_1/2 = 3 hours). ^bMetabolically cleared by CYP2D6 (polymorphic). Compared to extensive metabolizers (EM), individuals who are poor metabolizers (PM) have a lower CL/F, and a longer t_1/2 (7.6 ± 1.5 versus 2.8 ± 1.2 hours) and excrete more unchanged drug in urine (15 ± 7% versus 3.2 ± 3%) due to reduced hepatic metabolism. ^cC_{3 hours} following a single 100-mg oral dose in CYP2D6 EM and PM patients with hypertension. Plasma concentrations of the more active S-enantiomer are ~35% higher than the R-antipode in CYP2D6 EM. No stereochemical difference was observed in PM subjects. EC₅₀ for decreased heart rate during peak submaximal exercise testing was 16 ± 7 ng/mL; EC₅₀ for decreased systolic blood pressure during exercise testing was 25 ± 18 ng/mL.

References: Dayer P, et al. Interindividual variation of beta-adrenoceptor blocking drugs, plasma concentration and effect: Influence of genetic status on behaviour of atenolol, bopindolol and metoprolol. Eur J Clin Pharmacol, 1985, 28:149–153. Lennard MS, et al. Oxidation phenotype—A major determinant of metoprolol metabolism and response. N Engl J Med, 1982, 307:1558–1560. McGourty JC, et al. Metoprolol metabolism and debrisoquine oxidation polymorphism—Population and family studies. Br J Clin Pharmacol, 1985, 20:555–566.

Metronidazole^a

99 ± 8^b

↔ Crohn

10 ± 2

11 ± 3

1.3 ± 0.3

↓ LD, Neo

↔ Preg, RD, Crohn, Aged

0.74 ± 0.10

↔ RD, Crohn, LD

8.5 ± 2.9

↑ Neo, LD

↔ Preg, RD, Crohn, Child

PO: 2.8^c

VA: 11 ± 2^c

IV: 27 (11-41) μg/mL^c

PO: 19.8 μg/mL^c

VA: 1.9±0.2 μg/mL^c

^aActive hydroxylated metabolite accumulates in renal failure. ^bBioavailability is 67-82% for rectal suppositories and 53 ± 16% for intravaginal gel. ^cFollowing a single 100-mg dose of vaginal (VA) cream, a 100-mg IV infusion over 20 minutes three times daily to steady state, or a 100-mg oral dose three times daily to steady state.

Reference: Lau AM, et al. Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives. Clin Pharmacokinet, 1992, 23:328–364.

Micafungin^a

—

0.14 ± 0.03

↔ LD^b, RD^c

0.20 ± 0.03

14.6 ± 3.0

—

8.8 ± 1.8 μg/mL^d

^aUndergoes arylsulfatase-dependent metabolism and biliary excretion. ^bStudy in patients with moderate liver impairment; no difference in weight-adjusted clearance. ^cStudy in patients with CL_cr <30 mL/min. ^dFollowing a 100-mg IV infusion administered over 1 hour.

Reference: Hebert MF, et al. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease and volunteers with renal dysfunction. J Clin Pharmacol, 2005, 45:1145–1152.

Midazolam^a

44 ± 17^b

↑ LD

<1%

↓ Aged, RD

↔ Smk, LD

6.6 ± 1.8

↑ RD^c

↓ LD, Neo

↔ Obes, Smk, Child

1.1 ± 0.6

↑ Obes

↔ LD

↓ Neo

1.9 ± 0.6

↑ Aged, Obes, LD

↔ Smk

PO: 0.67 ± 0.45^d

IV: 113 ± 16 ng/mL^d

PO: 78 ± 27 ng/mL^d

^aMetabolically cleared exclusively by CYP3A. ^bUndergoes extensive first-pass metabolism by intestinal and hepatic CYP3A. Bioavailability appears to be dose dependent; 35-67% at15-mg, 28-36% at 7.5-mg, and 12-47% at 2-mg oral dose, possibly due to saturable first-pass intestinal metabolism. ^cIncreased CL due to increased plasma free fraction; unbound CL is unchanged. ^dFollowing a single 5-mg IV bolus or 10-mg oral dose.

References: Garzone PD, et al. Pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet, 1989, 76:337–364. Thummel KE, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther, 1996, 59:491–502.

Minocycline^a

95-100

11 ± 2

1.0 ± 0.3

↓ HL

1.3 ± 0.2^b

↓ HL

16 ± 2

↔ HL

PO: 2-4^c

IV: 3.5 μg/mL^c

PO: 2.3-3.5 μg/mL^c

^aCleared primarily by oxidative metabolism in the liver. ^bV_area reported. ^cFollowing a single 200-mg IV infusion (1 hour) or range of values following a 100-mg oral dose given twice a day to steady state.

Reference: Saivin S, et al. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet, 1988, 15:355–366.

Mirtazapine^a

50 ± 10

—

9.12 ± 1.14^b

↓ LD,^c RD^d

4.5 ± 1.7

16.3 ± 4.6^b,e

↓ LD,^c RD^d

1.5 ± 0.7^f

41.8 ± 7.7 ng/mL^f

^aData from healthy adult subjects. Metabolized by CYP2D6 and CYP1A2 (8-hydroxy) and CYP3A (N-desmethyl, N-oxide). ^bWomen of all ages exhibit a lower CL/F and longer t_1/2 than men. ^cCL/F reduced, hepatic impairment. ^dCL/F reduced, moderate to severe renal impairment. ^eThe t_1/2 of the (−)-enantiomer is approximately twice as long as the (+)-antipode; approximately 3-fold higher blood concentrations (+ versus −) are achieved. ^fFollowing a15-mg oral dose given once daily to steady state.

References: Fawcett J, et al. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord, 1998, 51:267–285. PDR54, 2000, p. 2109.

Mitoxantrone^a

—^b

13 ± 8

↓ LD

90 ± 42^c

β-phase: 1.1 ± 1.1^d

γ-phase: 72 ± 40^d

↑ LD

—

308 ± 133 ng/mL^e

^aData reported for patients treated for cancer. Information from older literature confounded by nonspecific assays. ^bFor parenteral administration only; usually given as a rapid IV infusion every 3 months. ^cReflects distribution into a "deep" tissue compartment. V_c is 0.3 ± 0.2 L/kg. ^dt_1/2 for the β-phase predicts time to steady state for short-term IV infusions. t_1/2 for the γ-phase predicts long-term persistence in the body. ^eFollowing a single 30-minute IV infusion of 12-14 mg/m².

References: Ehninger G, et al. Pharmacokinetics and metabolism of mitoxantrone. A review. Clin Pharmacokinet, 1990, 18:365–380. Hu OY, et al. Pharmacokinetic and pharmacodynamic studies with mitoxantrone in the treatment of patients with nasopharyngeal carcinoma. Cancer, 1992, 69:847–853.

Modafinil,^A Armodafinil

—

Rac: 3.7 ± 15

Arm: <10

Rac: 60

—

—^b

—^c

↓ LD^d, Aged

—^b

—^c

Rac: 13.6 ± 2.6

Arm: 13.0 ± 2.6

↑ LD^d

Rac: 2.5 ± 1.0^e

Arm: 1.8

Rac: 4.6 ± 0.7 μg/mL^e

Arm: 5.4 ± 1.6 μg/mL^e

^aModafinil is available either as a racemic mixture or as the pure (R)-enantiomer armodafinil. Pharmacokinetic data after dosing of racemate (Rac) or armodafinil (Arm) is reported. Modafinil is extensively metabolized in the liver to two major metabolites, modafinil acid and modafinil sulfone. ^bCL/F = 0.72 ± 0.10 mL/min/kg and V/F = 0.77 ± 0.11 L/kg after an oral dose of racemic modafinil. ^cThe exposure to Arm is 40% higher than that of racemic modafinil after equal oral doses. Arm CL/F = 0.47 mL/min/kg and V/F = 0.6 L/kg. ^dStudy in patients with moderate to severe liver impairment receiving oral racemic modafinil; CL/F reduced by 60% and steady-state concentrations doubled in patients with liver impairment. ^eFollowing a 200-mg single oral dose of modafinil or Arm.

References: Wong YN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol, 1999, 39:30–40. Wong YN, et al. Open-label, single-dose pharmacokinetic study of modafinil tablets and tolerability of modafinil tablets: Influence of age and gender in normal subjects. J Clin Pharmacol, 1999, 39:30–40. Drugs@FDA. Nuvigil label approved on 06/15/07. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed May 17, 2010.

Montelukast^a

<0.2

>99

0.70 ± 0.17

↓ LD^b

↔ Child^c

0.15 ± 0.02

4.9 ± 0.6

↑ LD^b

3.0 ± 1.0^d

542 ± 173 ng/mL^d

^aData from healthy adult subjects. No significant gender differences. Montelukast is metabolized by CYP3A4 and CYP2C9. ^bCL/F is reduced by 41%, mild to moderate hepatic impairment with cirrhosis. ^cSimilar plasma profile with 5-mg chewable versus 10-mg tablet in adults. ^dFollowing a single 10-mg oral dose.

References: PDR54, 2000, p. 1882. Zhao JJ, et al. Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers. Biopharm Drug Dispos, 1997, 18:769–777.

Morphine^a

PO: 24 ± 12

IM: ~100

4 ± 5

35 ± 2

↓ AVH, LD, Alb

24 ± 10

↔ Aged, LD, Child^b

↓ Neo, Burn, RD, Prem

3.3 ± 0.9

↔ LD, Neo

↓ RD

1.9 ± 0.5

↔ LD, RD, Child

↑ Neo, Prem

IM: 0.2-0.3^c

PO-IR: 0.5-1.5^c

PO-SR: 3-8^c

IV: 200-400 ng/mL^c

IM: ~70 ng/mL^c

PO-IR: 10 ng/mL^c

PO-SR: 7.4 ng/mL^c

^aActive metabolite, morphine-6-glucuronide; Urinary excretion = 14 ± 7%; t_1/2 = 4.0 ± 1.5 hours. Steady-state ratio of active metabolite to parent drug after oral dosing = 4.9 ± 3.8. In renal failure, t_1/2 increases to 50 ± 37 hours, resulting in significant accumulation of active glucuronide metabolite. ^bDecreased in children undergoing cardiac surgery requiring inotropic support. ^cFollowing a single 10-mg IV dose (bolus with 5-minute blood sample), a 10-mg/70-kg IM, a 10-mg/70-kg immediate-release oral (PO-IR) dose, or a 50-mg sustained-release oral dose (PO-SR). Minimum analgesic concentration is 15 ng/mL.

References: Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity: Morphine, methadone and naloxone. Clin Pharmacokinet, 1976, 1:219–230. Glare PA, et al. Clinical pharmacokinetics of morphine. Ther Drug Monit, 1991, 13:1–23.

Moxifloxacin^a

86 ± 1

21.9 ± 3.6

39.4 ± 2.4

2.27 ± 0.24

2.05 ± 1.15

15.4 ± 1.2

2.0 (0.5-6.0)^b

2.5 ± 1.3 μg/mL^b

^aData from healthy adult male subjects. Moxifloxacin is metabolized by ST and UGT. ^bFollowing a single oral 400-mg dose.

Reference: Stass H, et al. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. J Antimicrob Chemother, 1999, 43(suppl B):83–90.

Mycophenolate^a

MM: ~0

MPA: 94

MPA: <1

MPA: 97.5

↓ RD^b

MM: 120-163

MPA: 2.5 ± 0.4^c

↓ RD^b

↔ LD

MPA: 3.6-4^c

MM: <0.033

MPA: 16.6 ± 5.8

MPA: 1.1-2.2^d

MPA: 8-19 μg/mL^d

^aData from healthy adult male and female subjects and organ transplant patients. No significant gender differences. Mycophenolate mofetil (MM) is rapidly converted to the active mycophenolic acid (MPA) after IV and oral doses. Kinetic parameters refer to MM and MPA after a dose of MM. MPA metabolized by UGT to MPA-glucuronide (MPAG). MPA undergoes enterohepatic recycling; MPAG is excreted into bile and presumably is hydrolyzed by gut flora and reabsorbed as MPA. ^bAccumulation of MPA and MPAG and increased unbound MPA; severe renal impairment. ^cCL/F and V_area/F reported for MPA. ^dRange of mean MPA C_max and T_max from different studies following a 1- to 1.75-g oral dose given twice daily to steady state in renal transplant patients.

References: Bullingham R, et al. Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients. Br J Clin Pharmacol, 1996, 47:513–516. Bullingham RE, et al. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet, 1998, 34:429–455. Kriesche HUM, et al. MPA protein binding in uremic plasma: Prediction of free fraction. Clin Pharmacol Ther, 1999, 65:184. PDR54, 2000, pp. 2617–2618.

Nabumetone^a

~ 50

~ 99^b

0.37 ± 0.25^c

↔ Aged

0.79 ± 0.38^c

↔ Aged

23 ± 4

↑ RD

↔ Aged

Y: 4-5^d

E: 4-7^d

Y: 22-52 μg/mL^d

E: 37-70 μg/mL^d

^aData are for the active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA). The conversion of nabumetone to the active metabolite 6-MNA is mediated predominantly by CYP1A2. ^b99.7-99.8% over concentration range following multiple 1-g doses; 99.2-99.4% following multiple 200-mg doses. ^cCL/F and V_ss/F reported; calculated assuming a 70-kg body weight. Following IV dosing of 6-MNA, CL is 0.04-0.07 mL/min/kg and V_ss averages 0.11 L/kg. ^dRange of mean values from different studies following a 1-g oral dose given once daily for7-14 days to young healthy adults (Y) and elderly patients with arthritis (E).

References: Davies NM. Clinical pharmacokinetics of nabumetone. The dawn of selective cyclo-oxygenase-2 inhibition? Clin Pharmacokinet, 1997, 33:404–416. Hyneck ML. An overview of the clinical pharmacokinetics of nabumetone. J Rheumatol, 1992, 19(suppl 36):20–24. Turpeinen M, et al. A predominate role of CYP1A2 for the metabolism of nabumetone to the active metabolite, 6-methoxy-2-naphtylacetic acid, in human liver microsomes. Drug Metab Dispos, 2009, 37:1017–1024.

Naltrexone^a

20 ± 5

18.3 ± 1.4

↓ LD^b

16.1 ± 5.2

10.3 ± 3.3^c

↔ LD

1^d

15-64 ng/mL^d

^aNaltrexone has an active metabolite, 6β-naltrexol, that circulates at greater concentrations than naltrexone and has a 10-fold higher AUC than naltrexone after oral administration of naltrexone. ^bThe oral AUC of naltrexone was significantly increased in patients with liver impairment, whereas the AUC of 6β-naltrexol was not changed. ^cA t_1/2 of 2.7 hours after IV administration also reported. ^dFollowing a single 100-mg oral dose.

References: Bullingham RES, et al. Clinical pharmacokinetics of narcotic agonist-antagonist drugs. Clin Pharmacokinet, 1983, 8:332–343. Bertolotti M, et al. Effect of liver cirrhosis on the systemic availability of naltrexone in humans. J Hepatol, 1997, 27:505–511.

Naproxen^a

99^b

5-6

99.7 ± 0.1^c

↑ RD, Aged,^d LD

↓ RA, Alb

0.13 ± 0.02^e

↓ RD

↔ Aged,^d Cirr,^d Child

↑ RA

0.16 ± 0.02^e

↑ RD, RA, Child

↔ Aged, Child

14 ± 1

↔ RD, RA, Child

↑ Aged^d

T-IR: 2-4^f

T-CR: 5^f

S: 2.2 ± 2.1^f

T-IR: 37^f

T-CR: 94^f

S: 55 ± 14 μg/mL^f

^aMetabolically cleared by CYP2C9 (polymorphic) and CYP1A2. ^bEstimated bioavailability. ^cSaturable plasma protein binding yields apparent nonlinear elimination kinetics. ^dNo change in total CL, but a significant (50%) decrease in CL of unbound drug; it is thus suggested that dosing rate be decreased. A second study in elderly patients found a decreased CL and increased t_1/2 with no change in percent bound. ^eCL/F and V_area/F reported. ^fFollowing a single 250-mg dose of suspension (S) given orally to pediatric patients or a 250-mg immediate-release tablet (T-IR) or a 500-mg controlled-release tablet (T-CR) given to adults.

Reference: Wells TG, et al. Comparison of the pharmacokinetics of naproxen tablets andsuspension in children. J Clin Pharmacol, 1994, 34:30–33.

Niacin^a

—^b

↑ Food

12^c

—

14.6 ± 5.0^d

—

~0.15-0.25^e

ER: 4-5^f

ER (1 g): 0.6 μg/mL^f

ER (2 g): 15.5 μg/mL^f

^aNiacin (nicotinic acid) is metabolized to nicotinamide, which in turn is converted to the coenzyme NAD and other inactive metabolites. It also undergoes direct glycine conjugation to nicotinuric acid. ^bThe absolute bioavailability is not known. Niacin is well-absorbed but undergoes first-pass metabolism. Absorption is improved when taken with a low-fat meal. ^cRecovery of unchanged drug after multiple oral dose administration. ^dCL calculated from C_ss (6.6 ± 2.4 μg/mL) during an IV infusion of niacin. Niacin metabolic CL appears to be saturable. ^eEstimated from the terminal log-linear portion of a disappearance curve following the end of a 0.1-mg/kg/min IV infusion in two subjects. ^fFollowing a single 1-g or 2-g oral dose of extended-release (ER) NIASPAN. Markedly disproportional increases in plasma concentrations with increasing dose.

References: Ding RW, et al. Pharmacokinetics of nicotinic acid-salicylic acid interaction. Clin Pharmacol Ther, 1989, 46:642–647. PDR58, 2004, p. 1797. Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol, 2000, 86:35L–40L.

Nifedipine^a

50 ± 13

↑ LD, Aged

↔ RD

96 ± 1

↓ LD, RD

7.0 ± 1.8

↓ LD, Aged

↔ RD, Smk

0.78 ± 0.22

↑ LD, RD, Aged

↔ Smk

1.8 ± 0.4^b

↑ LD, RD, Aged

↔ Smk

IR: 0.5 ± 0.2^c

ER: ~6^cs

IR: 79 ± 44 ng/mL^c

ER: 35-49 ng/mL^c

^aMetabolically cleared by CYP3A; undergoes significant first-pass metabolism. ^bLonger apparent t_1/2 after oral administration because of absorption limitation, particularly for extended-release (ER) formulations. ^cMean following a single 10-mg immediate-release (IR) capsule given to healthy male adults or a range of steady-state concentrations following a60-mg ER tablet given daily to healthy male adults. Levels of 47 ± 20 ng/mL were reportedto decrease diastolic pressure in hypertensive patients.

References: Glasser SP, et al. The efficacy and safety of once-daily nifedipine: The coat-core formulation compared with the gastrointestinal therapeutic system formulation in patients with mild-to-moderate diastolic hypertension. Nifedipine Study Group. Clin Ther, 1995, 17:12–29. Renwick AG, et al. The pharmacokinetics of oral nifedipine—A population study. Br J Clin Pharmacol, 1988, 25:701–708. Soons PA, et al. Intraindividual variability in nifedipine pharmacokinetics and effects in healthy subjects. J Clin Pharmacol, 1992, 32:324–331.

Nitrofurantoin

87 ± 13

47 ± 13

62 ± 4

9.9 ± 0.9

↑ Alkaline urine

0.58 ± 0.12

1.0 ± 0.2

↔ Alkaline urine

2.3 ± 1.4^a

428 ± 146 ng/mL^a

^aFollowing a single 50-mg oral dose (tablet) given to fasted healthy adults. No changes when taken with a meal.

Reference: Hoener B, et al. Nitrofurantoin disposition. Clin Pharmacol Ther, 1981, 29:808–816.

Nitroglycerin^a

PO: <1

SL: 38 ± 26^b

Top: 72 ± 20

—

195 ± 86^c

3.3 ± 1.2^c,d

2.3 ± 0.6 min

SL: 0.09 ± 0.03^e

Top: 3-4^e

TD: 2^e

IV: 3.4 ± 1.7 ng/mL^e

SL: 1.9 ± 1.6 ng/mL^e

^aDinitrate metabolites have weak activity compared to nitroglycerin (<10%), but because of a prolonged t_1/2 (~40 min), they may accumulate during administration of sustained-release preparations to yield concentrations in plasma 10- to 20-fold greater than parent drug. ^bFollowing sublingual (SL) dose rinsed out of mouth after 8 minutes. Rinse contained 31 ± 19% of the dose. ^cFollowing a 40- to 100-minute IV infusion. ^dV_area reported. ^eSteady-state concentration following a 20-54 μg/min IV infusion over 40-100 minutes or a 0.4-mg SL dose. Levels of 1.2-11 ng/mL associated with a 25% drop in capillary wedge pressure in patients with CHF. T_max for topical (Top) and transdermal (TD) preparations also reported.

References: Noonan PK, et al. Incomplete and delayed bioavailability of sublingual nitroglycerin. Am J Cardiol, 1985, 55:184–187. PDR54, 2000, p. 1474. Thadani U, et al. Relationship of pharmacokinetic and pharmacodynamic properties of the organic nitrates. Clin Pharmacokinet, 1988, 15:32–43.

Nortriptyline^a

51 ± 5

2 ± 1

92 ± 2

↑ HL

7.2 ± 1.8^b

↓ Aged, Inflam

↔ Smk, RD

18 ± 4^c

31 ± 13^b

↑ Aged

↔ RD

7-10

138 (40-350) nM^d

^aActive metabolite, 10-hydroxynortriptyline, accumulates to twice the concentration of nortriptyline in extensive metabolizers. Formation of 10-hydroxynortriptyline is catalyzed by CYP2D6 (polymorphic). ^bFor poor metabolizers, CL/F is lower (5.3 versus 19.3 mL/min/kg) and t_1/2 longer (54 versus 21 hours) than that of extensive metabolizers. ^cV_area reported. ^dMean following a 125-mg oral dose given once daily to healthy adults to steady state. Antidepressant effect observed at levels of 190-570 nM. Appears less effective at plasmaconcentrations >570 nM.

References: Dalen P, et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther, 1998, 63:444–452. Jerling M, et al. Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6—An evaluation with the nonparametric maximum likelihood method. Br J Clin Pharmacol, 1994, 38:453–462. Ziegler VE, et al. Nortriptyline plasma levels and therapeutic response. Clin Pharmacol Ther, 1976, 20:458–463.

Olanzapine^a

~60^b

7.3

6.2 ± 2.9^c

↔ RD, LD

16.4 ± 5.1^c

33.1 ± 10.3

↑ Aged

6.1 ± 1.9^d

12.9 ± 7.5 ng/mL^d

^aData from male and female schizophrenic patients. Metabolized primarily by UGT, CYP1A2, and flavin-containing monooxygenase. ^bBioavailability estimated from parent-metabolite recovery data. ^cSummary of CL/F and V_area/F for 491 subjects receiving an oral dose. CL/F segregates by sex (F/M) and smoking status (NS/S): M, S > F, S > M, NS > F, NS. ^dFollowing a single 9.5 ± 4-mg oral dose to healthy male subjects; C_max,ss ~20 ng/mL following a 10-mg oral dose given once daily.

References: Callaghan JT, et al. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet, 1999, 37:177–193. Kassahun K, et al. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos, 1997, 25:81–93. PDR54, 2000, p. 1649.

Olmesartan^a

35-50

0.31 ± 0.05

0.36 ± 0.18

13.7 ± 5.6

1.5 (1-2.5)^b

1083 ± 283 ng/mL^b

^aOlmesartan is administered as a prodrug, olmesartan medoxomil. Pharmacokinetic data for olmesartan is reported. ^bFollowing 40-mg/day olmesartan medoxomil for 10 days.

References: Drugs@FDA. Benicar label approved on 07/13/05. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed May 17, 2010. Rohatgi S, et al. Pharmacokinetics of amlodipine and olmesartan after administration of amlodipine besylate and olmesartan medoxomil in separate dosage forms and as a fixed-dose combination. J Clin Pharmacol, 2008, 48:1309–1322.

Ondansetron

62 ± 15^a

↑ Aged, LD^b, Fem

73 ± 2

5.9 ± 2.6

↓ Aged, LD^b, Fem

↑ Child

1.9 ± 0.05

↔ Aged, LD^c

3.5 ± 1.2

↑ Aged, LD^c

↓ Child

PO: 1.0 (0.8-1.5)^c

IV: 102 (64-136) ng/mL^c

PO: 39 (31-48)^c

^aIn 26 cancer patients (62 ± 10 years), F = 86 ± 26%. ^bMild to moderate liver impairment. ^cMean (95% confidence interval) values following a single dose of 0.15 mg/kg IV or an oral dose of 8 mg given three times daily for 5 days to healthy adults.

Reference: Roila F, et al. Ondansetron clinical pharmacokinetics. Clin Pharmacokinet, 1995, 29:95–109.

Oxaliplatin^a

—^b

—^c

90^d

49 (41-64)^e

1.5 (1.1-2.1)

0.32 (0.27-0.46)^f

—

Ox: 0.33 (0.28-0.38)

μg Pt/mL

PtDC: 0.008 (0.004-0.014)

μg Pt/mL^g

^aOxaliplatin is an organoplatinum complex; Pt is coordinated with diaminocyclohexane (DACH) and an oxalate ligand as a leaving group. Oxaliplatin (Ox) undergoes non-enzymatic biotransformation to reactive derivatives, notably Pt(DACH)Cl₂ (PtDC). Antitumor activity and toxicity are thought to relate to the concentration of oxaliplatin and PtDC in plasma ultrafiltrate (i.e., unbound concentration). ^bFor IV administration only. ^c~54% of the platinum eliminated is recovered in urine. ^dBinding to plasma proteins is irreversible. ^eCL of total platinum is much lower; ~2-4 mL/min/kg. ^fThe elimination of platinum species in plasma follows a triexponential pattern. The quoted t_1/2 reflects the t_1/2 of the first phase, which is the clinically relevant phase. The t_1/2 for the slower two phases are 17 and 391 hours. ^gSteady-state plasma ultrafiltrate concentration of Ox and PtDC after an 85-mg/m² IV infusion over2 hours during cycles 1 and 2.

References: PDR58, 2004, pp. 3024–3025. Shord SS, et al. Oxaliplatin biotransformation and pharmacokinetics: A pilot study to determine the possible relationship to neurotoxicity. Anticancer Res, 2002, 22:2301–2309.

Oxcarbazepine^a

—

O: <1

HC: 27

—

HC: 45

O: 67.4^b

HC: ↓ RD,^c Aged

HC: ↑ Child^d

—

O: ~2

HC: 8-15

HC: ↑ RD, Aged

HC: 2-4^e

HC: 8.5 ± 2.0 μg/mL^e

^aData from healthy adult male subjects. No significant gender differences. Oxcarbazepine (O) undergoes extensive first-pass metabolism to an active metabolite, 10-hydroxycarbamazepine (HC). Reduction by cytosolic enzymes is stereoselective (80% S-enantiomer, 20%R-enantiomer), but both show similar pharmacological activity. ^bCL/F for O reported. HC eliminated by glucuronidation. ^cAUC for HC increased, moderate to severe renal impairment. ^dAUC for HC decreased, children <6 years of age. ^eFollowing a 300-mg oral oxcarbazepine dose given twice daily for 12 days.

References: Battino D, et al. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine and felbamate. Clin Pharmacokinet, 1995, 29:341–369. Lloyd P, et al. Clinical pharmacology and pharmacokinetics of oxcarbazepine. Epilepsia, 1994, 35(suppl 3):S10–S13. Rouan MC, et al. The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites. Eur J Clin Pharmacol, 1994, 47:161–167. van Heiningen PN, et al. The influence of age on the pharmacokinetics of the antiepileptic agent oxcarbazepine. Clin Pharmacol Ther, 1991, 50:410–419.

Oxybutynin^a

1.6-10.9

—

8.1 ± 2.3^b

1.3 ± 0.4^b

IV: 1.9 ± 0.35^b,c

IR: 5.0 ± 4.2^d

XL: 5.2 ± 3.7^d

IR:12.4 ± 4.1 ng/mL^d

XL: 4.2 ± 1.6 ng/mL^d

^aData from healthy female subjects. No significant gender differences. Racemic mixture; anticholinergic activity resides predominantly with R-enantiomer; no stereoselectivity exhibited for anti-spasmodic activity. Oxybutynin undergoes extensive first-pass metabolism to N-desethyloxybutynin (DEO), an active, anticholinergic metabolite. Metabolized primarily by intestinal and hepatic CYP3A. Racemic oxybutynin kinetic parameters reported. ^bData reported for a 1-mg IV dose, assuming a 70-kg body weight. A larger volume (2.8 L/kg) and longer t_1/2 (5.3 hours) reported for a 5-mg IV dose. ^cExhibits a longer apparent t_1/2 following oral dosing due to absorption rate-limited kinetics: immediate-release (IR) t_1/2 = 9 ± 2 hours; extended-release (XL) t_1/2 = 14 ± 3 hours. The apparent t_1/2 for DEO was 4.0 ± 1.4 hours and 8.3 ± 2.5 hours for the IR and XL formulations, respectively. ^dFollowing a dose of 5-mg IR given three times daily or 15-mg XL given once daily for 4 days. Peak DEO levels at steady state were 45 and 23 ng/mL for IR and XL, respectively.

References: Gupta SK, et al. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol, 1999, 39:289–296. PDR54, 2000, p. 507.

Oxycodone^a

CR: 60-87^b

IR: 42 ± 7^b

—^c

12.4 (9.2-15.4)

2.0 (1.1-2.9)

2.6 (2.1-3.1)^d

CR: 3.2 ± 2.2^e

IR: 1.6 ± 0.8^e

CR: 15.1 ± 4.7 ng/mL^e

IR: 15.5 ± 4.5 ng/mL^e

^aOxycodone is metabolized primarily by CYP3A4/5, with a minor contribution from CYP2D6. Oxymorphone is an active metabolite produced by CYP2D6-mediated O-dealkylation. The circulating concentrations of oxymorphone are too low to contribute significantly to the opioid effects of oxycodone. Data from healthy male and female subjects reported. ^bValues reported for OXYCONTIN [oxycodone controlled release (CR)] and immediate-release (IR) tablets. ^cUp to 19% excreted unchanged after an oral dose. ^dThe apparent t_1/2 for the CR oral formulation is ~5 hours; this most likely reflects absorption-limited terminal elimination kinetics. ^eFollowing 10 mg of OXYCONTIN (CR) given twice daily to steady state or a 5-mg IR tablet given every 6 hours to steady state.

References: Benziger DP, et al. Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate-release oxycodone solution. J Pharm Sci, 1996, 85:407–410. PDR58, 2004, pp. 2854–2855. Takala A, et al. Pharmacokinetic comparison of intravenous and intranasal administration of oxycodone. Acta Anaesthesiol Scand, 1997, 47:309–312.

Paclitaxel^a

Low

5 ± 2

88-98^b

5.5 ± 3.5

↔ Child

2.01 ± 1.2

↔ Child

31 ± 1^c

—

0.85 ± 0.21 μM^d

^aMetabolized by CYP2C8 and CYP3A, and substrate for P-glycoprotein. ^bBinding of drug to dialysis filtration devices may lead to overestimation of protein binding fraction (88% suggested). ^cAverage accumulation t_1/2; longer terminal t_1/2 up to 50 hours are reported. ^dSteady-state concentration during a 250-mg/m² IV infusion given over 24 hours to adult cancer patients.

Reference: Sonnichsen DS, et al. Clinical pharmacokinetics of paclitaxel. Clin Pharmacokinet, 1994, 27:256–269.

Paliperidone^a

28 (oral ER)^b,c

59 (51-67) (oral ER)

↓ LD

3.70 ± 1.04^d

↑ LD^e

9.1^d (oral ER)

28.4 ± 5.1^d (oral ER)

25-49 days (IM PP)^f

22 (2.0-24)^d (oral ER)

13 days (IM PP)

10.7 ± 3.3 ng/mL^d (oral ER)

^aPaliperidone, otherwise known as the 9-hydroxy active metabolite of risperidone, is marketed as an oral extended-release (ER) tablet (INVEGA) or in the form of its water-insoluble palmitate ester as a once-monthly long-acting IM injection (INVEGA SUSTENNA). Paliperidone is a racemate; its enantiomers have similar pharmacological profiles. The (+) and (–)-enantiomers of paliperidone interconvert, reaching an AUC (+) to (–) ratio of ~1.6 at steady state. ^bHigh-fat/ high-caloric meal increased C_max and AUC by 60% and 54%, respectively. ^cNo data on the absolute bioavailability of IM paliperidone palmitate (IM PP). The initiation regimen for INVEGA SUSTENNA (234 mg/156 mg in the deltoid muscle on day 1/day 8) produces paliperidone concentrations matching the range observed with 6- to 12-mg oral ER paliperidone. ^dAt steady-state during once-daily doses of 3 mg, assuming an average body weight of 73 kg. V_z is estimated from CL/F and t_1/2. ^ePatients with moderate hepatic impairment showed a modest increase in clearance and plasma free fraction with no significant change in unbound AUC. ^fThe apparent long terminal t_1/2 of paliperidone following IM depot injection reflects the slow dissolution of paliperidone palmitate and release of active paliperidone.

References: Boom S, et al. Single- and multiple-dose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release. J Clin Pharmacol, 2009, 49:1318–1330. Drugs@FDA. Invega label approved on 4/27/07; Invega Sustenna label approved on 7/31/09. Available at: http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/. Accessed on January 1, 2010.

Pantoprazole^a

77 (67-89)

—^b

2.8 ± 0.9

↓ LD

↔ RD

0.17 ± 0.04

1.1 ± 0.4

↑ LD

↔ Aged

2.6 ± 0.9

2.5 ± 0.7 μg/mL^c

^aPantoprazole is cleared primarily by CYP2C19 (polymorphic)-dependent metabolism. Poor metabolizers (PM) exhibit profound differences in CL (lower) and t_1/2 (higher), compared to extensive metabolizers (EM). Pantoprazole is available as a racemic mixture of (+) and (–) isomers. In CYP2C19 EM, no significant differences in the pharmacokinetics of (+) and (–) pantoprazole were observed, whereas in CYP2C19 PM, the CL of (–) pantoprazole wassignificantly greater than that of (+) pantoprazole. ^bNo unchanged drug recovered in urine. ^cFollowing a single 40-mg oral dose.

References: Drugs@FDA. Protonix label approved on 11/12/09. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 26, 2009. Huber R, et al. Pharmacokinetics of lansoprazole in man. Int J Clin Pharmacol Ther, 1996, 34:185–194. Pue MA, et al. Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects. Eur J Clin Pharmacol, 1993, 44:575–578. Tanaka M, et al. Stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor, in extensive and poor metabolizers of S-mephenytoin. Clin Pharmacol Ther, 2001, 69:108–113.

Paroxetine

Dose dependent^a

8.6 ± 3.2^a,b

↓ LD, Aged

17 ± 10^c

17 ± 3^d

↑ LD, Aged

5.2 ± 0.5^e

EM: ~130 nM^e

PM: ~220 nM^e

^aMetabolized by CYP2D6 (polymorphic); undergoes time- and dose-dependent autoinhibition of metabolic CL in extensive metabolizers (EM). ^bCL/F reported for multiple dosing in EM. Single dose data are significantly higher. In CYP2D6 poor metabolizers (PM), CL/F = 5.0 ± 2.1 mL/min/kg for multiple dosing. ^cV_area/F reported. ^dData reported for multiple dose in EM. In PM, t_1/2 = 41 ± 8 hours. ^eEstimated mean C_max following a 30-mg oral dose given once daily for 14 days to adults phenotyped as CYP2D6 EM and PM. There is a significant disproportional accumulation of drug in blood when going from single to multiple dosing due to autoinactivation of CYP2D6.

References: PDR54, 2000, p. 3028. Sindrup SH, et al. The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther, 1992, 51:278–287.

Phenobarbital

100 ± 11

24 ± 5^a

↔ LD, AVH

51 ± 3

↓ Neo

↔ Preg, Aged

0.062 ± 0.013

↑ Preg, Child, Neo

↔ Smk

0.54 ± 0.03

↑ Neo

99 ± 18

↑ LD, Aged

↓ Child

↔ Epilepsy, Neo

2-4^b

13.1 ± 4.5 μg/mL^b

^aPhenobarbital is a weak acid (pK_a = 7.3); urinary excretion is increased at an alkaline pH;it also is reduced with decreased urine flow. ^bMean steady-state concentration following a90-mg oral dose given daily for 12 weeks to patients with epilepsy. Levels of 10-25 μg/mL provide control of tonic-clonic seizures, and levels of at least 15 μg/mL provide control of febrile convulsions in children. Levels >40 μg/mL can cause toxicity; 65-117 μg/mL produce stage III anesthesia—comatose but reflexes present; 100-134 μg/mL produce stage IV anesthesia—no deep-tendon reflexes.

References: Bourgeois BFD. Phenobarbital and primidone. In: Wyllie E, ed. The Treatmentof Epilepsy: Principles and Practice, 2nd ed. Philadelphia, Williams & Wilkins, 1997, pp. 845–855. Browne TR, et al. Studies with stable isotopes II: Phenobarbital pharmacokinetics during monotherapy. J Clin Pharmacol, 1985, 25:51–58.

Phenytoin^a

90 ± 3

2 ± 8

89 ± 23

↓ RD, Hep, Alb, Neo, AVH, LD, NS, Preg, Burn

↔ Obes, Smk, Aged

V_max = 5.9 ± 1.2

mg · kg^–1 · day^–1

↓ Aged, ↑ Child

K_m = 5.7 ± 2.9 mg/L^b

↔ Aged, ↓ Child

↑ NS, RD^c

↓ Prem^c

↔ AVH, LTh, HTh, Smk^c

0.64 ± 0.04^d

↑ Neo, NS, RD

↔ AVH, LTh, HTh

6-24^e

↑ Prem^c

↓ RD^c

↔ AVH, LTh, HTh, Smk^c

3-12^f

0-5 μg/mL (27%)^f

5-10 μg/mL (30%)^f

10-20 μg/mL (29%)^f

20-30 μg/mL (10%)^f

>30 μg/mL (6%)^f

^aMetabolized predominantly by CYP2C9 (polymorphic) and also by CYP2C19 (polymorphic); exhibits saturable kinetics with therapeutic doses. ^bSignificantly decreased in the Japanese population. ^cComparison of CLs and t_1/2s with similar doses in normal subjects and patients; nonlinear kinetics not considered. ^dV_area reported. ^eApparent t_1/2 is dependent on plasma concentration. ^fPopulation frequency of total phenytoin concentrations following a 300-mg oral dose (capsule) given daily to steady state. Total levels >10 μg/mL associated with suppression of tonic-clonic seizures. Nystagmus can occur at levels >20 μg/mL and ataxia at levels >30 μg/mL.

References: Eldon MA, et al. Pharmacokinetics and tolerance of fosphenytoin and phenytoin administered intravenously to healthy subjects. Can J Neurol Sci, 1993, 20(suppl 4):S180. Levine M, et al. Therapeutic drug monitoring of phenytoin. Rationale and current status. Clin Pharmacokinet, 1990, 79:341–358. Tozer TN, et al. Phenytoin. In: Evans WE, et al., eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 3rd ed. Vancouver, WA, Applied Therapeutics, 1992, pp. 25-1–25-44.

Pioglitazone^a

—

Negligible

>99

1.2 ± 1.7^b

0.63 ± 0.41^b

11 ± 6^c

P: 3.5 (1-4)^d

M-III: 11 (2-48)^d

M-IV: 11 (4-16)^d

P: 1.6 ± 0.2 μg/mL^d

M-III: 0.4 ± 0.2

μg/mL^d

M-IV: 1.4 ± 0.5

μg/mL^d

^aData from healthy male and female subjects and patients with type 2 diabetes. Pioglitazone (P) is metabolized extensively by CYP2C8, CYP3A4, and other CYP isozymes. Two major metabolites (M-III and M-IV) accumulate in blood and contribute to the pharmacological effect. ^bCL/F and V_area/F reported. CL/F is lower in women than in men. ^cSteady-state t_1/2 of M-III and M-IV is 29 and 27 hours, respectively. ^dFollowing a 45-mg oral dose given once daily for 10 days.

References: Budde K, et al. The pharmacokinetics of pioglitazone in patients with impaired renal function. Br J Clin Pharmacol, 2003, 55:368–374. PDR58, 2004, p. 3186.

Posaconazole^a

—

↔ RD

11.7 ± 6.4^b

↔ RD

11.9^b

21.6 ± 8.4

↔ RD

4 (3-12)

324 ± 161 ng/mL^c

↔ RD

^a~66% of an oral posaconazole dose is excreted unchanged in feces. It is unclear whether this represents significant biliary excretion or unabsorbed drug. ^bCL/F and V_d/F reported. ^cFollowing a single 400-mg dose of an oral suspension.

References: Courtney R, et al. Posaconazole pharmacokinetics, safety, and tolerability insubjects with varying degrees of chronic renal disease. J Clin Pharmacol, 2005, 45:185–192. Dodds Ashley ES, et al. Pharmacokinetics of posaconazole administered orally or by nasogastric tube in healthy volunteers. Antimicrob Agents Chemother, 2009, 53:2960–2964.

Pramipexole^a

>90^b

~90

8.2 ± 1.4^b

↓ Aged, RD,^c PD^d

7.3 ± 1.7^b

11.6 ± 2.57

↑ Aged, RD

1-2

M: 1.6 ± 0.23 ng/mL^e

F: 2.1 ± 0.25 ng/mL^e

^aData from healthy adult male and female subjects. No significant gender differences. ^bBioavailability estimated from urinary recovery of unchanged drug. CL/F and V_area/F reported. ^cCL/F reduced, moderate to severe renal impairment. ^dParkinson's disease (PD); CL/F reduced with declining renal function. ^eFollowing a 0.5-mg oral dose given three times daily for 4 days to male (M) and female (F) adults.

References: Lam YW. Clinical pharmacology of dopamine agonists. Pharmacotherapy, 2000, 20:17S–25S. PDR54, 2000, p. 2468. Wright CE, et al. Steady-state pharmacokinetic properties of pramipexole in healthy volunteers. J Clin Pharmacol, 1997, 37:520–525.

Pramlintide^a

30-40%^b

–

~60^c

Low: 14.9 ± 3.9^d

High: 14.5 ± 4.0^d

↔ RD^e

0.43

0.71

IV: 0.4-0.75

SC: 0.5-0.83

0.32-0.35^f

Low: 21 ± 3 pmol/L^f

High: 77 ± 22 pmol/L^f

^aPramlintide is a synthetic peptide analog of amylin for the treatment of both type 1 and type 2 diabetes. It is metabolized in the kidneys to at least one primary active metabolite: Des-lys(1)pramlintide (2-37 pramlintide) with a t_1/2 similar to that of the parent drug. ^bSC administration with greater variability in response when the injection is into the arm compared to into the abdomen or thigh. ^cNot extensively bound to blood cells or albumin. ^dBased on IV infusion of a low dose of 30 μg for type 1 diabetes and a high dose of 100 μg for type 2 diabetes. ^eStudy in patients with moderate to severe renal impairment. No data in end-stage RD. ^fFollowing a low SC dose of 30 μg and a high SC dose of 100 μg.

References: Colburn WA, et al. Pharmacokinetics and pharmacodynamics of AC137 (25,28,29 triproamylin, human) after intravenous bolus and infusion doses in patients with insulin-dependent diabetes. J Clin Pharmacol, 1996, 36:13–24. Drugs@FDA. Symlin label approved on 9/25/07. Available at: http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/. Accessed on August 1, 2009. Kolterman OG, et al. Effect of 14 days' subcutaneous administration of the human amylin analogue, pramlintide (AC137), on an intravenous insulin challenge and response to a standard liquid meal in patients with IDDM. Diabetologia, 1996, 39:492–499.

Pravastatin

18 ± 8

47 ± 7

43-48

13.5 ± 2.4

↓ LD

↔ Aged, RD^a

0.46 ± 0.04

0.8 ± 0.2^b

↔ Aged, RD^a

1-1.4^c

28-38 ng/mL^c

^aAlthough renal CL decreases with reduced renal function, no significant changes in CL/F or t_1/2 are seen following oral dosing as a result of the low and highly variable bioavailability. ^bA longer t_1/2 = 1.8 ± 0.8 hour reported for oral dosing; probably rate limited by absorption. ^cRange of mean values from different studies following a single 20-mg oral dose.

References: Corsini A, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther, 1999, 84:413–428. Desager JP, et al. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet, 1996, 31:348–371. Quion JA, et al. Clinical pharmacokinetics of pravastatin. Clin Pharmacokinet, 1994, 27:94–103.

Praziquantel^a

—^b

Negligible

80-85

5 mg/kg: 467^c

40-60 mg/kg: 57-222^c

↓ LD^d

50 mg/kg: 9.55 ± 2.86

5 mg/kg: 0.8-1.5^c

40-60 mg/kg: 1.7-3.0^c

↑ LD

1.5-1.8^e

0.8-6.3 μg/L^e

^aData from male and female patients with schistosomiasis. ^bAbsolute bioavailability is not known. Praziquantel is well absorbed (80%) but undergoes significant first-pass metabolism (hydroxylation), the extent of which appears to be dose dependent. ^cCL/F and V_ss/F reported; CL/F and t_1/2 are dose dependent. ^dCL/F reduced, moderate to severe hepatic impairment. ^eRange of mean values from different studies following a single 40- to 60-mg/kg oral dose.

References: Edwards G, et al. Clinical pharmacokinetics of anthelmintic drugs. Clin Pharmacokinet, 1988, 15:67–93. el Guiniady MA, et al. Clinical and pharmacokinetic study of praziquantel in Egyptian schistosomiasis patients with and without liver cell failure. Am J Trop Med Hyg, 1994, 51:809–818. Jung H, et al. Clinical pharmacokinetics of praziquantel. Proc West Pharmacol Soc, 1991, 34:335–340. Sotelo J, et al. Pharmacokinetic optimisation of the treatment of neurocysticercosis. Clin Pharmacokinet, 1998, 34:503–515. Watt G, et al. Praziquantel pharmacokinetics and side effects in Schistosoma japonicum-infected patients with liver disease. J Infect Dis, 1988, 157:530–535.

Prednisolone

82 ± 13

↔ Hep, Cush, RD, Crohn, Celiac, Smk, Aged

↓ HTh

26 ± 9^a

↑ Aged, HTh

90-95 (<200 ng/mL)^b

~70 (>1 μg/mL)

↓ Alb, NS, Aged, HTh, LD

↔ Hep

1.0 ± 0.16^c

↔ Hep, Cush, Smk, CRI, NS,^d

HTh^d

↓ Aged,^d LD^d

0.42 ± 0.11^e

↔ Hep, Cush, Smk, RD, CRI, NS^d

↓ HTh,^d

Aged, Obes^d

2.2 ± 0.5

↔ Hep, Cush, Smk, RD, CRI, NS^d

↓ HTh^d

↑ Aged^d

1.5 ± 0.5^f

458 ± 150 ng/mL^f

^aPrednisolone and prednisone are interconvertible; an additional 3 ± 2% is excreted as prednisone. ^bExtent of binding to plasma proteins is dependent on concentration over range encountered. ^cTotal CL increases as protein binding is saturated. CL of unbound drug increases slightly but significantly with increasing dose. ^dChanges are for unbound drug.^eV increases with dose due to saturable protein binding. ^fFollowing a 30-mg oral dose given twice daily for 3 days to healthy adult male subjects. The ratio of prednisolone/prednisone is dose dependent and can vary from 3-26 over a prednisolone concentration range of 50-800 ng/mL.

References: Frey BM, et al. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet, 1990, 19:126–146. Rohatagi S, et al. Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration. J Clin Pharmacol, 1997, 37:916–925.

Prednisone

80 ± 11^a

↔ Hep, Cush, RD, Crohn, Celiac, Smk, Aged

3 ± 2^b

↔ HTh

75 ± 2^c

3.6 ± 0.8^d

↔ Hep

0.97 ± 0.11^d

↔ Hep

3.6 ± 0.4^d

↔ Smk, Hep

P: 2.1-3.1^e

PL: 1.2-2.6^e

P: 62-81 ng/mL^e

PL: 198-239 ng/mL^e

^aMeasured relative to equivalent IV dose of prednisolone (PL). ^bAn additional 15 ± 5% excreted as PL. ^cIn contrast to PL, there is no dependence on concentration. ^dKinetic values for prednisone (P) often are reported in terms of values for PL, its active metabolite. However, the values cited here pertain to P. ^eRange of mean data for P and PL following a single 10-mg oral dose given as different proprietary formulations to healthy adults.

References: Gustavson LE, et al. The macromolecular binding of prednisone in plasma of healthy volunteers including pregnant women and oral contraceptive users. J Pharmacokinet Biopharm, 1985, 13:561–569. Pickup ME. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet, 1979, 4:111–128. Sullivan TJ, et al. Comparative bioavailability: Eight commercial prednisone tablets. J Pharmacokinet Biopharm, 1976, 4:157–172.

Pregabalin^a

≥90^b

90-99

0.96-1.2^c

↓ RD^d

0.5

5-6.5

1^b

8.5 μg/mL^e

^aPregabalin undergoes minimal metabolism; an N-methylated metabolite has been identified in urine and accounts for 0.9% of oral dose. >90% of dose is excreted in urine as unchanged drug. Pregabalin pharmacokinetics is dose independent and predictable from single to multiple dosing. ^bBioavailability does not vary with dose up to 600 mg. T_max is delayed from 1 hour to 3 hours and C_max decreased by 25-30% when pregabalin is given with food. No change in AUC or extent of absorption is noted. ^cMean renal clearance in healthy young subjects ranges from 67 to 81 mL/min and assuming 70-kg body weight. ^dPregabalin clearance is proportional CL_cr; hence, dosage can be adjusted in accordance to CL_cr in renal dysfunction. Plasmapregabalin decreased by ~50% after 4 hours of hemodialysis. ^eSteady-state concentration in healthy subjects receiving 200-mg pregabalin every 8 hours.

References: Bialer M, et al. Progress report on new antiepileptic drugs: A summary of the fifth Eilat conference (EILAT V). Epilepsy Res, 2001, 43:11–58. Brodie MJ, et al. Pregabalin drug interaction studies: Lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy. Epilepsia, 2005, 46:1407–1413. Physicians' Desk Reference, 63rd ed. Montvale, NJ, Physicians' Desk Reference Inc., 2008, pp. 2527–2534.

Procainamide^a

83 ± 16

67 ± 8

↓ CHF, COPD, CP, LD

16 ± 5

CL = 2.7CL_cr + 1.7 + 3.2 (fast)^b or + 1.1 (slow)^b

↑ Child

↓ MI

↔ CHF, Tach, Neo

1.9 ± 0.3

↓ Obes

↔ RD, Child, Tach, CHF

3.0 ± 0.6

↑ RD^c

↓ Child, Neo

↔ Obes, Tach, CHF

M: 3.6^d

F: 3.8^d

M: 2.2 μg/mL^d

F: 2.9 μg/mL^d

^aActive metabolite, N-acetylprocainamide (NAPA); CL = 3.1 ± 0.4 mL/min/kg, V =1.4 ± 0.2 L/kg, and t_1/2 = 6.0 ± 0.2 hours. ^bCL calculated using units of mL/min/kg for CL_cr. CL depends on NAT2 acetylation phenotype. Use a mean value of 2.2 if phenotype unknown. ^ct_1/2 for procainamide and NAPA increased in patients with RD. ^dLeast square mean values following 1000-mg oral dose given twice daily to steady state in male (M) and female (F) adults. Mean peak NAPA concentrations were 2.0 and 2.2 μg/mL for male and female adults, respectively; T_max = 4.1 and 4.2 hours, respectively.

References: Benet LZ, et al. Die renale Elimination von Procainamide: Pharmacokinetik bei Niereninsuffizienz. In: Braun J, et al., eds. Die Behandlung von Herzrhythmusstorungen bei Nierenkranken. Basel, Karger, 1984, pp. 96–111. Koup JR, et al. Effect of age, gender, and race on steady state procainamide pharmacokinetics after administration of Procanbid sustained-release tablets. Ther Drug Monit, 1998, 20:73–77.

Promethazine^a

PO: 27.9 ± 19.8^b

Rectal: 21.7-23.4^c

0.64 ± 0.49

15.7 ± 5.7

13.4 ± 3.6^d

12.2 ± 2.2

PO: 2.8 ± 1.4^e

Rectal: 8.2 ± 3.4

PO: 21.8 ± 14.0 ng/mL^e

Rectal: 11.3 ± 8.5 ng/mL

^aPromethazine undergoes ring-hydroxylation mediated by CYP2D6, N-demethylation by CYP2B6, and S-oxidation to a sulfoxide. Promethazine is well absorbed following oral administration (>80%) but is subject to first-pass metabolism, which explains its low systemic availability. ^bOral bioavailability at 75-mg dose as compared to IV bolus. ^cBioavailability of two commercial rectal suppositories at a 50-mg dose compared to an IM dose. ^dSteady-state volume. ^eData for a 50-mg oral dose of promethazine in solution. ^fFollowing a 50-mg dose of promethazine rectal suppository.

References: Drugs@FDA. AcipHex label approved on 6/30/08. Available at: http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ Accessed on August 2, 2009. Koytchev R, et al. Absolute bioavailability of chlorpromazine, promazine and promethazine. Arzneimittelforschung, 1994, 44:121–125. Schwinghammer TL, et al. Comparison of the bioavailability of oral, rectal and intramuscular promethazine. Biopharm Drug Dispos, 1984, 5:185–194. Sharma A, et al. Classic histamine H1 receptor antagonists: A critical review of their metabolic and pharmacokinetic fate from a bird's eye view. Curr Drug Metab, 2003, 4:105–129. Stavchansky S, et al. Bioequivalence and pharmacokinetic profile of promethazine hydrochloride suppositories in humans. J Pharm Sci, 1987, 76:441–445. Taylor G, et al. Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man. Br J Clin Pharmacol, 1983, 15:287–293.

Propofol^a

—^b

—

98.3-98.8^c

27 ± 5

↑ Child,^d

↓ Aged^e

↔ LD

1.7 ± 0.7^f

↑ Child^d

↓ Aged^e

3.5 ± 1.2^f

—

SS: 3.5 ± 0.06 μg/mL^g

E: 1.1 ± 0.4 μg/mL^g

^aData from patients undergoing elective surgery and healthy volunteers. Propofol is extensively metabolized by UGTs. ^bFor IV administration only. ^cFraction bound in whole blood. Concentration dependent; 98.8% at 0.5 μg/mL and 98.3 at 32 μg/mL. ^dCL and central volume increased in children 1-3 years of age. ^eCL and central volume decreased in elderly patients. ^fV_area is much larger than V_ss. A much longer terminal t_1/2 was reported following prolonged IV infusion. Concentration producing anesthesia after infusion to steady state (SS) and at emergence (E) from anesthesia.

References: Mazoit JX, et al. Binding of propofol to blood components: Implications for pharmacokinetics and for pharmacodynamics. Br J Clin Pharmacol, 1999, 47:35–42. Murat I, et al. Pharmacokinetics of propofol after a single dose in children aged 1–3 years with minor burns. Comparison of three data analysis approaches. Anesthesiology, 1996, 84:526–532. Servin F, et al. Pharmacokinetics of propofol infusions in patients with cirrhosis. Br J Anaesth, 1990, 65:177–183.

Propranolol^a

26 ± 10

↑ Cirr

<0.5

87 ± 6^b

↑ Inflam, Crohn, Preg, Obes

↔ RD, Fem, Aged

↓ LD

16 ± 5^c,d

↑ Smk, HTh

↓ Hep, LD, Obes, Fem

↔ Aged, RD

4.3 ± 0.6^c

↑ Hep, HTh, LD

↓ Crohn

↔ Aged, RD, Obes, Fem, Preg

3.9 ± 0.4^c

↓ Hep, LD, Obes, Fem

↔ Aged, RD, Smk, Preg

P: 1.5^e

HP: 1.0^e

P: 49 ± 8 ng/mL^e

HP: 37 ± 9 ng/mL^e

^aRacemic mixture. For S-(–)-enantiomer (100-fold more active) compared to R-(+)-enantiomer, CL is 19% lower and V_area is 15% lower because of a higher degree of protein binding (18% lower free fraction); hence, there is no difference in t_1/2. Active metabolite, 4-hydroxypropranolol (HP). ^bDrug is bound primarily to α₁-acid glycoprotein, which is elevated in a number of inflammatory conditions. ^cBased on blood measurements; blood-to-plasma concentration ratio = 0.89 ± 0.03. ^dCYP2D6 catalyzes the formation of HP; CYP1A2 is responsible for most of the N-desisopropyl metabolite; UGT catalyzes the major conjugation pathway of elimination. ^eFollowing a single 80-mg oral dose given to healthy adults. Plasmaaccumulation factor was 3.6-fold after 80 mg was given four times daily to steady state. A concentration of 20 ng/mL gave a 50% decrease in exercise-induced cardioacceleration. Anti-anginal effects manifest at 15-90 ng/mL. A concentration up to 1000 ng/mL may be required for control of ventricular arrhythmias.

References: Colangelo PM, et al. Age and propranolol stereoselective disposition in humans. Clin Pharmacol Ther, 1992, 57:489–494. Walle T, et al. 4-Hydroxypropranolol and its glucuronide after single and long-term doses of propranolol. Clin Pharmacol Ther, 1980, 27:22–31.

Pseudoephedrine^a

~100

43-96^b

—

7.33^b,c

2.64-3.51^c

4.3-8^b,c

IR: 1.4-2^d

CR: 3.8-6.1^d

IR: 177-360 ng/mL^d

CR: 265-314 ng/mL^d

^aData from healthy adult male and female subjects. ^bAt a high urinary pH (>7.0), pseudoephedrine is extensively reabsorbed; t_1/2 increases, and CL decreases. ^cCL/F, V/F, and t_1/2 reported for oral dose. ^dRange of mean values from different studies following a single 60-mg immediate-release tablet or syrup (IR), or 120-mg controlled-release capsule (CR) oral dose.

Reference: Kanfer I, et al. Pharmacokinetics of oral decongestants. Pharmacotherapy, 1993, 13:116S–128S.

Pyrazinamide^a

—^b

4-14^c

1.1 (0.2-2.3)^d

↑ Child

0.57 (0.13-1.04)^d

6 (2-23)

↓ Child

1-2^e

35 (19-103) μg/mL^e

^aPyrazinamide is hydrolyzed in the liver to an active metabolite, 2-pyrazinoic acid. Reported peak 2-pyrazinoic acid concentrations range from 0.1- to 1-fold that of the parent drug. Pyrazinamide data reported are for male and female adults with tuberculosis. ^bAbsolute bioavailability is not known, but the drug is well absorbed based on recovery of parent drug and metabolites (70%). ^cRecovery unchanged following an oral dose; the recovery of pyrazinoic acid is 37 ± 5%. ^dCL/F and V_area/F reported. ^eFollowing a 15- to 53-mg/kg daily oral dose to steady state.

References: Bareggi SR, et al. Clinical pharmacokinetics and metabolism of pyrazinamidein healthy volunteers. Arzneimittelforschung, 1987, 37:849–854. Lacroix C, et al. Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacol, 1989, 36:395–400. PDR58, 2004, p. 766. Zhu M, et al. Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacotherapy, 2002, 22:686–695.

Quetiapine^a

↑ Food

<1%

↓ Aged

↔ RD

↓ LD

10 ± 4

1-1.8

278 ng/mL^b

^aNo significant gender differences. Extensively metabolized through multiple pathways, including sulfoxidation, N- and O-dealkylation catalyzed by CYP3A4. Two minor active metabolites. ^bFollowing a 250-mg oral dose given daily for 23 days in patients with schizophrenia.

References: Goren JL, et al. Quetiapine, an atypical antipsychotic. Pharmacotherapy, 1998, 18:1183–1194. PDR54, 2000, p. 563.

Quinapril^a

QT (Q): 52 ± 15^b

Q (Q): 3.1 ± 1.2^c

QT (QT): 96^d

Q/QT: 97

QT (QT): 0.98 ± 0.22^d

↓ RD

QT (QT): 0.19 ± 0.04^d

Q (Q): 0.8-0.9^c

QT (QT): 2.1-2.9^d

↑ RD

Q (Q): 1.4 ± 0.8^e

QT (Q): 2.3 ± 0.9^e

Q (Q): 207 ± 89 ng/mL^e

QT (Q): 923 ± 277 ng/mL^e

^aHydrolyzed to its active metabolite, quinaprilat. Pharmacokinetic data for quinapril (Q) and quinaprilat (QT) following oral Q and IV QT administration are presented. ^bAbsolute bioavailability based on plasma QT concentrations. ^cData for Q following a 2.5- to 80-mg oral Q dose. ^dData for QT following a 2.5-mg IV QT dose. The t_1/2 of QT after dosing Q is similar. ^eFollowing a single 40-mg oral Q dose. No accumulation of QT with multiple dosing.

References: Breslin E, et al. A pharmacodynamic and pharmacokinetic comparison of intravenous quinaprilat and oral quinapril. J Clin Pharmacol, 1996, 36:414–421. Olson SC, et al. The clinical pharmacokinetics of quinapril. Angiology, 1989, 40:351–359. PDR58, 2004, p. 2516.

Quinidine^a

Sulfate: 80 ± 15

Gluconate: 71 ± 17

18 ± 5

↔ CHF

87 ± 3

↓ LD, Hep, Neo, Preg

↔ RD, CRI, HL, Aged

4.7 ± 1.8^b

↓ CHF, Aged

↔ LD, Smk

2.7 ± 1.2

↓ CHF

↑ LD

↔ Aged

6.2 ± 1.8

↑ Aged, LD

↔ CHF, RD

IR: 1-3^c

ER: 6.3 ± 3.2^c

IV: 2.9 ± 1.0 μg/mL^c

IR: ~1.3 μg/mL^c

ER: 0.53 ±0.22 μg/mL^c

^aActive metabolite, 3-hydroxyquinidine (t_1/2 = 12 ± 3 hours; percent bound in plasma = 60 ± 10%). ^bMetabolically cleared primarily by CYP3A. ^cFollowing a 400-mg IV dose (22-minute infusion) of quinidine gluconate or a single 400-mg oral dose of immediate-release (IR) quinidine sulfate or a 300-mg dose of extended-release (ER) quinidine sulfate (QUINIDEX) to healthy adults. Specific assay methods for quinidine show >75% reduction in frequency of premature ventricular contractions at levels of 0.7-5.9 μg/mL, but active metabolite was not measured; therapeutic levels of 2-7 μg/mL were reported for nonspecific assays.

References: Brosen K, et al. Quinidine kinetics after a single oral dose in relation to the sparteine oxidation polymorphism in man. Br J Clin Pharmacol, 1990, 29:248–253. Sawyer WT, et al. Bioavailability of a commercial sustained-release quinidine tablet compared to oral quinidine solution. Biopharm Drug Dispos, 1982, 3:301–310. Ueda CT, et al. Absolute quinidine bioavailability. Clin Pharmacol Ther, 1976, 20:260–265.

Quinine^a

76 ± 11

N-A: 12-20

M-A: 33 ± 18

N-A: ~85-90^b

M-A: 93-95^b

↓ Neo

↔ Preg

N-A: 1.9 ± 0.5

M-A: 0.9-1.4

M-C: 0.4-1.4

↔ Preg,^c RD^c

↑ Smk

↓ Aged

N-A: 1.8 ± 0.4

M-A: 1.0-1.7

M-C: 1.2-1.7

↓ Preg^c

↔ RD^c

N-A: 11 ± 2

M-A: 11-18

M-C: 12-16

↓ Preg,^c Smk

↔ RD^c

↑ Hep, Aged

PO: 3.5-8.4^d

Adults

IV: 11 ± 2 μg/mL^d

PO: 7.3-9.4 μg/mL^d

Children

IV: 8.7-9.4 μg/mL^d

PO: 7.3 ± 1.1 μg/mL^d

^aData from normal adults (N-A) and range of means from different studies of adults (M-A) or children (M-C) with malaria reported. ^bCorrelates with serum α₁-acid glycoprotein levels. Binding is increased in severe malaria. ^cFrom patients with malaria. ^dFollowing a single10-mg/kg dose given as a 0.5- to 4-hour IV infusion or orally (PO) to children or adults with malaria. A level >0.2 μg/mL for unbound drug is targeted for treatment of falciparum malaria. Oculotoxicity and hearing loss/tinnitus associated with unbound concentrations >2 μg/mL.

References: Edwards G, et al. Clinical pharmacokinetics in the treatment of tropical diseases. Some applications and limitations. Clin Pharmacokinet, 1994, 27:150–165. Krishna S, et al. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin Pharmacokinet, 1996, 30:263–299.

Rabebrazole^a

52^b

0^b

95-98

4.2 ± 1.2^c

0.37^c

1.0 ± 0.6^c

3.8-4.6

EM: 437 ± 241 ng/mL^d

PM: 600 ± 319 ng/mL^d

^aRabeprazole is primarily converted non-enzymatically to rabeprazole-thioether; some of it is oxidized to desmethylrabeprazole and rabeprazole sulfone by CYP2C19 and CYP3A4, respectively. CYP2C19 genetic polymorphism has a modest effect on rabeprazole clearance. Rabeprazole possesses an asymmetric sulfur center; the enantiomers inhibit H⁺/K⁺-ATPase with equal potency in vitro. ^b~90% of radiolabeled oral dose is recovered in urine, indicating near-complete gastrointestinal absorption. Incomplete systemic availability is due to instability and first-pass metabolism of rabeprazole. ^cBased on data from a 20-mg IV dose of rabeprazole in subjects with unknown CYP2C19 genotype or phenotype, most likely reflecting characteristics of extensive metabolizers (EM). Elimination t_1/2 up to 2-3 hours has been observed in poor metabolizers (PM) of CYP2C19 following oral rabeprazole. ^dAt steady state during a 20-mg once-a-day regimen for duodenal ulcer.

References: Yasuda S, et al. Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status. Clin Pharmacol Ther, 1995, 58:143–154. Yasuda S, et al. Pharmacokinetic properties of E3810, a new proton pump inhibitor, in healthy male volunteers. Int J Clin Pharmacol Ther, 1994, 32:466–473. Setoyama T, et al. Mass balance study of [¹⁴C] rabeprazole following oral administration in healthy subjects. Int J Clin Pharmacol Ther, 2006, 44:557–565. Setoyama T, et al. Pharmacokinetics of rabeprazole following single intravenous and oral administration to healthy subjects. Int J Clin Pharmacol Ther, 2005, 43:37–42.

Raloxifene^a

2^b

<0.2

>95

735 ± 338^c

↔ RD, Aged

↓ LD

2348 ± 1220^c

28 (11-273)

6^d

0.5 ± 0.3 ng/mL^d

^aData from postmenopausal women. Undergoes extensive first-pass metabolism (UGT catalyzed) and enterohepatic recycling. ^b~60% absorption from the gastrointestinal tract; not significantly affected by food. ^cCL/F and V/F reported for an oral dose. ^dFollowing a single 1-mg/kg oral dose.

References: Hochner-Celnikier D. Pharmacokinetics of raloxifene and its clinical application. Eur J Obstet Gynecol Reprod Biol, 1999, 85:23–29. PDR54, 2000, p. 1583.

Raltegravir^a

≥31.8 ± 9.4^b

8.8 ± 4.7

16.1 (11.4, 22.6)^c

↔ RD

↑ Hemodialysis

↔ LD (modest)

α: 0.92 ± 0.21^d

β: 12.5 ± 4.6^d

1.0^e

4.5 (2.0, 10.2) μM^e

^aRaltegravir undergoes O-glucuronidation mediated largely by UGT1A1 and to a lesser extent by UGT1A3 and UGT1A9. Raltegravir AUC is only modestly elevated in individuals with UGT1A1*28/*28 genotype compared to *1/*1 genotype. ^bThe absolute oral bioavailability of raltegravir has not been determined. This minimum extent of oral absorption is based upon recovery of radioactivity in urine following oral administration of ¹⁴C-labeled raltegravir in healthy human subjects. ^cGeometric mean (95% confidence interval) of pharmacokinetic parameters following a single 400-mg oral dose. Apparent oral clearance (CL/F) is listed. ^dPlasma concentration time course of raltegravir exhibits multiphasic washout kinetics. Initial (α) and terminal (β) t_1/2s are reported because the early phase accounts for a large portion of the AUC from time 0 to ∞. ^eMedian for T_max and geometric mean (95% confidence interval) for C_max following a 400-mg twice-daily monotherapy regimen for 10 days in treatment-naive patients with HIV-1 infection.

References: Drugs@FDA. Isentress label approved on 7/8/09. Available at: http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/. Accessed on August 22, 2009. Kassahun K, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos, 2007, 35:1657–1663. Wenning LA, et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother, 2008, 52:3253–3258. Wenning LA, et al. Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms. Clin Pharmacol Ther, 2009, 85:623–627.

Ramelteon^a

1.8^b

<0.1%

883 ± 857^c

↓ Aged

↓ LD^d

↔ RD

P: 1.3 ± 0.5^e

M: 2.3 ± 0.5^e

↑ Aged

P: 1.6 ± 0.5

P: 6.9 ± 7.8 ng/mL^e,f

M: 110 ± 29 ng/mL^e,f

↑ Aged

^aRamelteon undergoes primary oxidative metabolism followed by glucuronidation as secondary metabolism. CYP1A2 is the major enzyme involved in oxidative metabolism; CYP3A and CYP2C9 also are involved as minor enzymes. Remarkable elevation in C_max and AUC were observed with the concurrent administration of the strong CYP1A2 inhibitor fluvoxamine. The M-II metabolite contributes to the hypnotic effects of ramelteon. M-II has 1/5th to 1/10th the affinity of ramelteon as an agonist for the melatonin receptors (MT-1 and MT-2); however, it circulates at 20- to 100-fold higher concentrations relative to ramelteon. ^bPoor systemic availability of ramelteon is due to extensive first-pass metabolism. C_max and AUC are elevated by a high-fat meal; T_max is slightly delayed. ^cIntersubject variability is notably large.^dFour- and 10-fold elevation in AUC in mild and moderate hepatic impairment. ^eP = parent drug; M = M-II metabolite. ^fC_max following a single 16-mg oral dose of ramelteon in young adult subjects. There is no measurable accumulation of parent drug or active metabolite because of their short elimination t_1/2.

References: Drugs@FDA. Rozerem label approved on 10/20/08. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on August 23, 2009. Greenblatt DJ, et al. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT 1 and MT2. J Clin Pharmacol, 2006, 47:485–496. McGechan A, et al. Ramelteon. CNS Drugs, 2005, 19:1057–1065.

Ramipril^a

R (R): 28^b

RT (R): 48^b

R (R): <2^c

RT (R): 13 ± 6^c

R: 73 ± 2

RT: 56 ± 2

R (R): 23^d

RT: —^e

—

R (R): 5 ± 2

RT (R): 9-18^f

↑ RD

R (R): 1.2 ± 0.3^g

RT (R): 3.0 ± 0.7^g

R (R): 43.3 ± 10.2 ng/mL^g

RT (R): 24.1 ± 5.6 ng/mL^g

^aHydrolyzed to its active metabolite, ramiprilat (RT). Pharmacokinetic data for ramipril (R) and RT following oral and IV R administration are presented. ^bBased on plasma AUC of R and RT after IV and oral R administration. ^cFollowing an oral dose of R. ^dCL/F of R calculated from reported AUC data. ^eNo data available; mean renal CL of RT is ~1.1 mL/min/kg. ^ft_1/2 for the elimination phase reported. A longer terminal t_1/2 of ~120 hours most likely corresponds to the release of drug from ACE; contributes to the duration of effect, but does not contribute to systemic drug accumulation. ^gFollowing a single 10-mg oral dose.

References: Eckert HG, et al. Pharmacokinetics and biotransformation of 2-[N-[(S)-l-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(lS,3S,5S)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (Hoe 498) in rat, dog and man. Arzneimittelforschung, 1984, 34:1435–1447. Meisel S, et al. Clinical pharmacokinetics of ramipril. Clin Pharmacokinet, 1994, 26:7–15. PDR58, 2004, p. 2142. Song JC, et al. Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: An update. Clin Pharmacokinet, 2002, 41:207–224. Thuillez C, et al. Pharmacokinetics, converting enzyme inhibition and peripheral arterial hemodynamics of ramipril in healthy volunteers. Am J Cardiol, 1987, 59:38D–44D.

Ranitidine

52 ± 11

↑ LD

↔ RD

69 ± 6

↓ RD

15 ± 3

10.4 ± 1.1

↓ RD, Aged

↓ Burn

1.3 ± 0.4

↔ Cirr, RD

↓ Burn

2.1 ± 0.2

↑ RD, Cirr, Aged

↔ Burn

2.1 ± 0.31^a

462 ± 54 ng/mL^a

^aFollowing a single 150-mg oral dose given to healthy adults. IC₅₀ for inhibition of gastric acid secretion is 100 ng/mL.

Reference: Gladziwa U, et al. Pharmacokinetics and pharmacodynamics of H₂-receptorantagonists in patients with renal insufficiency. Clin Pharmacokinet, 1993, 24:319–332.

Remifentanil^a

—^b

Negligible

40-60

↔ RD, LD

↓ Aged^c

0.3-0.4

↓ Aged^c

↔ RD, LD

0.13-0.33

↔ RD, LD

—

~20 ng/mL^d

^aData from healthy adult male subjects and patients undergoing elective surgery. Undergoes rapid inactivation by esterase-mediated hydrolysis; resulting carboxy metabolite has low activity. ^bFor IV administration only. ^cCL and V decreased slightly in the elderly. ^dMeanCL_min following a 5-μg/kg IV dose (1-minute infusion). Cp₅₀ for skin incision is 2 ng/mL (determined in the presence of nitrous oxide).

References: Egan TD, et al. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology, 1998, 89:562–573. Glass PS, et al. A review of the pharmacokinetics and pharmacodynamics of remifentanil. Anesth Analg, 1999, 89:S7–S14.

Repaglinide^a

56 ± 7

0.3-2.6

97.4

9.3 ± 6.8

↓ RD,^b LD^c

0.52 ± 0.17

0.8 ± 0.2

↓ LD

0.25-0.75^d

47 ± 24 ng/mL^d

^aData from healthy adult male subjects. Undergoes extensive oxidative and conjugative metabolism; CYP3A4 has been implicated in the formation of the major (60% of dose) metabolite. ^bCL/F reduced, severe renal impairment. ^cCL/F reduced, moderate to severe LD. ^dFollowing a single 4-mg oral dose (tablet).

References: Hatorp V, et al. Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease. J Clin Pharmacol, 2000, 40:142–152. Hatorp V, et al. Unavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers. Int J Clin Pharmacol Ther, 1998, 36:636–641. Marbury TC, et al. Pharmacokinetics of repaglinide in subjects with renal impairment. Clin Pharmacol Ther, 2000, 67:7–15. van Heiningen PN, et al. Absorption, metabolism and excretion of a single oral dose of ¹⁴C-repaglinide during repaglinide multiple dosing. Eur J Clin Pharmacol, 1999, 55:521–525.

Ribavirin^a

45 ± 5

35 ± 8

0^b

5.0 ± 1.0^c

9.3 ± 1.5

28 ± 7^c

RT: 3 ± 1.8^d

R: 11.1 ± 1.2 μM^d

RT: 15.1 ± 12.8 μM^d

^aValues reported for studies conducted in asymptomatic HIV-positive men. ^bAt steady state, red blood cell–to-plasma concentration ratio is ~60. ^cFollowing multiple oral dosing, CL/F decreases by >50%, and a long terminal t_1/2 of 150 ± 50 hours is observed. ^dFollowing a 1200-mg oral ribavirin capsule (R) given daily for 7 days to adult subjects seropositive for HIV or a 600-mg oral REBETRON dose given twice daily to steady state to adults with hepatitis Cinfection.

References: Morse GD, et al. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother, 1997, 47:169–174. PDR54, 2000, p. 2836. Roberts RB, et al. Ribavirin pharmacodynamics in high-risk patients for acquired immunodeficiency syndrome. Clin Pharmacol Ther, 1987, 42:365–373.

Rifampin^a

—^b

7 ± 3

↑ Neo

60-90

3.5 ± 1.6^c

↑ Neo, ↓ RD^d

↔ Aged

0.97 ± 0.36

↑ Neo

↔ Aged

3.5 ± 0.8^c

↑ Hep, Cirr, AVH, RD^d

↔ Child, Aged

1-3^e

6.5 ± 3.5 μg/mL^e

^aActive desacetyl metabolite. ^bAbsolute bioavailability is not unknown, although some studies indicate complete absorption. Such reports presumably refer to rifampin plus its desacetyl metabolite because considerable first-pass metabolism is expected. ^ct_1/2 is shorter (1.7 ± 0.5) and CL/F is higher after repeated administration. Rifampin is a potent enzyme (CYP3A and others) inducer and appears to autoinduce its own metabolism. ^dNot observed with 300-mg doses, but pronounced differences with 900-mg doses. t_1/2 is longer with high single doses. ^eFollowing a 600-mg dose given once daily for 15-18 days to patients with tuberculosis.

Reference: Israili ZH, et al. Pharmacokinetics of antituberculosis drugs in patients. J Clin Pharmacol, 1987, 27:78–83.

Riluzole^a

64 (30-100)

↓ Food^b

5.5 ± 0.9

↓ LD

3.4 ± 0.6

14 ± 6

0.8 ± 0.5^c

173 ± 72 ng/mL^c

^aEliminated primarily by CYPlA2-dependent metabolism; metabolites are inactive. Involvement of CYP1A2 may contribute to ethnic (lower CL/F in Japanese) and gender (lower CL in women) differences and inductive effects of smoking (higher CL in smokers). ^bHigh-fat meal. ^cFollowing a 50-mg oral dose given twice daily to steady state.

References: Bruno R, et al. Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis. Clin Pharmacol Ther, 1997, 62:518–526. Le Liboux A, et al. Single- and multiple-dose pharmacokinetics of riluzole in white subjects. J Clin Pharmacol, 1997, 37:820–827. PDR58, 2004, p. 769. Wokke J. Riluzole. Lancet, 1996, 348:795–799.

Risperidone^a

PO: 66 ± 28^b

IM: 103 ± 13

3 ± 2^b

89^c

5.4 ± 1.4^b

↓ RD,^a Aged^d

1.1 ± 0.2

3.2 ± 0.8^a,b

↑ RD,^a Aged^d

R: ~l^e

R: 10 ng/mL^e

TA: 45 ng/mL^e

^aThe active metabolite, 9-hydroxyrisperidone, is the predominant circulating species in extensive metabolizers and is equipotent to parent drug. 9-Hydroxyrisperidone has a t_1/2 of 20 ± 3 hours. In extensive metabolizers, 35 ± 7% of an IV dose is excreted as this metabolite; its elimination is primarily renal and therefore correlates with renal function. ^bFormation of9-hydroxyrisperidone is catalyzed by CYP2D6. Parameters reported for extensive metabolizers. In poor metabolizers, F is higher; ~20% of an IV dose is excreted unchanged, 10% as the 9-hydroxy metabolite; CL is slightly <1 mL/min/kg, and t_1/2 is similar to that of the active metabolite, ~20 hours. ^c77% for 9-hydroxyrisperidone. ^dChanges in elderly subjects due to decreased renal function affecting the elimination of the active metabolite. ^eMean steady-state C_min for risperidone (R) and total active (TA) drug, risperidone + 9-OH-risperidone, following a 3-mg oral dose given twice daily to patients with chronic schizophrenia. No difference in total active drug levels between CYP2D6 extensive and poor metabolizers.

References: Cohen LJ. Risperidone. Pharmacotherapy, 1994, 14:253–265. Heykants J, et al. The pharmacokinetics of risperidone in humans: A summary. J Clin Psychiatry, 1994, 55(suppl):13–17.

Ritonavir^a

—^b

↑ Food

3.5 ± 1.8

98-99

SD: 1.2 ± 0.4^c

MD: 2.1 ± 0.8^c

↓ Child, LD^d

0.41 ± 0.25^c

3-5^c

↓ LD^d

2-4^e

11 ± 4 μg/mL^e

^aRitonavir is extensively metabolized primarily by CYP3A4. It also appears to induce its own CL with single-dose (SD) to multiple-dose (MD) administration. ^bAbsolute bioavailability unknown (>60% absorbed); food elicits a 15% increase in oral AUC for capsule formulation. ^cCL/F, V_area/F, and t_1/2 reported for oral dose. ^dCL/F reduced slightly and t_1/2 increased slightly, moderate liver impairment. ^eFollowing a 600-mg oral dose given twice daily to steady state.

References: Hsu A, et al. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet, 1998, 35:275–291. PDR54, 2000, p. 465.

Rivastigmine^a

72 (22-119)^b

↑ Food, Dose

Negligible

13 ± 4^c

1.5 ± 0.6^c

1.4 ± 0.4^c,d

1.2 ± 1.0^e

↓ Food

26 ± 10 ng/mL^e

↓ Food

^aRivastigmine is metabolized by cholinesterase. No apparent gender differences. ^bFollowing a 6-mg oral dose. Bioavailability increases with dose; following a 3-mg dose, the median bioavailability is 36%. ^cIV dose of 2 mg. ^dThe pharmacodynamic t_1/2 is ~10 hours due to tight binding to acetylcholinesterase. ^eFollowing oral administration of a 6-mg capsule. C_max increases more than proportionally at doses >3 mg.

References: Hossain M, et al. Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type. Clin Pharmacokinet, 2002, 41:225–234. Williams BR, et al. A review of rivastigmine: A reversible cholinesterase inhibitor. Clin Ther, 2003, 25:1634–1653.

Rizatriptan^a

F: 28 ± 9^b

M: 29^b

F: 12.3 ± 1.4^b

M: 18.9 ± 2.8^b

↓ LD,^c RD^d

F: 1.5 ± 0.2

M: 2.2 ± 0.4

F: 2.2

M: 2.4

SD: 0.9 ± 0.4^e

MD: 4.8 ± 0.7^e

SD: 20 ± 4.9 ng/mL^e

MD: 37 ± 13 ng/mL^e

^aData from healthy adult male (M) and female (F) subjects. Oxidative deamination catalyzed by MAO-A is the primary route of elimination. N-desmethyl rizatriptan (DMR) is a minor metabolite (~14%) that is active and accumulates in blood. ^bEvidence of minor dose-dependent metabolic CL and urinary excretion. ^cCL/F reduced, moderate hepatic impairment. ^dCL/F reduced, severe renal impairment. ^eFollowing a 10-mg single (SD) and multiple (MD) oral dose (10 mg every 2 hours × 3 doses × 4 days). DMR C_max is 8.5 and 26.2 ng/mL with SD and MD, respectively.

References: Goldberg MR, et al. Rizatriptan, a novel 5-HT_1B/1D agonist for migraine: Single- and multiple-dose tolerability and pharmacokinetics in healthy subjects. J Clin Pharmacol, 2000, 40:74–83. Lee Y, et al. Pharmacokinetics and tolerability of intravenous rizatriptan in healthy females. Biopharm Drug Dispos, 1998, 19:577–581. PDR54, 2000, p. 1912. Vyas KP, et al. Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans. Drug Metab Dispos, 2000, 28:89–95.

Ropinirole^a

<10

~40

11.2 ± 5.0^b

↓ Aged^c

↔ RD

7.5 ± 2.4^b

6^b

1.0 (0.5-6.0)^d

↑ Food

7.4 (2.4-13) ng/mL^d

↓ Food

^aData from male and female patients with Parkinson's disease. Metabolized primarily by CYP1A2 to inactive N-deisopropyl and hydroxy metabolites. ^bCL/F, V_d/F, and t_1/2 reported for oral dose. ^cCL/F reduced but dose titrated to desired effect. ^dFollowing a 2-mg oral dose given three times daily to steady state.

References: Bloomer JC, et al. In vitro identification of the P450 enzymes responsible for the metabolism of ropinirole. Drug Metab Dispos, 1997, 25:840–844. PDR54, 2000, p. 3037. Taylor AC, et al. Lack of a pharmacokinetic interaction at steady state between ropinirole and L-dopa in patients with Parkinson's disease. Pharmacotherapy, 1999, 79:150–156.

Rosiglitazone^a

Negligible

99.8

↓ LD^b

0.68 ± 0.16^c

(0.49)

↓ LD^d

↔ RD

0.25 ± 0.08^c

(0.21)

3-4^c

↓ LD

1.0^d

598 ± 117 ng/mL^d

^aData from male and female patients with NIDDM. No significant gender differences. Metabolized primarily by CYP2C8. ^bReduced CL/F and CL/F_unbound, moderate to severe liver impairment. ^cCL/F, V_d/F, and t_1/2 reported for oral dose. Shown in parentheses are mean values from a population pharmacokinetic analysis. ^dFollowing a single 8-mg oral dose.

References: Baldwin SJ, et al. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol, 1999, 48:424–432. Patel BR, et al. Population pharmacokinetics of rosiglitazone (R) in phase III clinical trials. Clin Pharmacol Ther, 2000, 67:123. PDR54, 2000, p. 2981. Thompson K, et al. Pharmacokinetics of rosiglitazone are unaltered in hemodialysis patients [abstract]. Clin Pharmacol Ther, 1999, 65:186.

Rosuvastatin^a

20 (17-23)

30 ± 7

10.5 ± 4.7

↓ RD^b

1.7 ± 0.5

20 ± 6

3 (l-6)^c

4.6 ± 2.1 ng/mL^c

^aEliminated primarily by biliary excretion; also appears to be actively transported into the liver by an organic anion transport protein (OATP2/SLC21A6). Data from healthy men reported; no significant gender or age differences. ^bReduced CL/F in patients with severe renal impairment. ^cFollowing a 10-mg oral dose taken once daily for 10 days.

References: Martin PD, et al. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther, 2003, 25:2553–2563. Martin PD, et al. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. Br J Clin Pharmacol, 2002, 54:472–477. Product labeling: Crestor^® tablets (rosuvastatin calcium). Wilmington, DE, Astra-Zeneca Pharmaceuticals LP, 2003. Schneck DW, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther, 2004, 75:455–463.

Selegiline^a

Negligible^b

Negligible

94^c

~1500^b

160^d

1.9

1.91 ± 1.0^e

S: 0.7 ± 0.4^f

DS: ~1 hr

S: 1.1 ± 0.4 ng/mL^f

DS: ~15 ng/mL^f

^aMAO-B active metabolite: l-(–)-desmethylselegiline. ^bExtensive first-pass metabolism; estimate of CL/F reported. ^cBlood-to-plasma concentration ratio = 1.3-2.2 for parent drug and ~0.55 for N-desmethyl metabolite. ^dCL/F for N-desmethylselegiline, assuming quantitative conversion of parent to this metabolite. ^eFor parent and N-desmethyl metabolite. t_1/2s for methamphetamine (major plasma species) and amphetamine are 21 and 18 hours, respectively. ^fMean data for selegiline (S) and its active metabolite, N-desmethylselegiline (DS), following a single 10-mg oral dose given to adults.

Reference: Heinonen EH, et al. Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites. Clin Pharmacol Ther, 1994, 56:742–749.

Sertraline

—^a

98-99

38 ± 14^b

↓ Aged, LD

—

↑ Aged, LD

M: 6.9 ± 1.0^c

F: 6.7 ± 1.8^c

M: 118 ± 22 ng/mL^c

F: 166 ± 65 ng/mL^c

↔ Aged

^aAbsolute bioavailability is not known (>44% absorbed); undergoes extensive first-pass metabolism to essentially inactive metabolites; catalyzed by multiple CYP isoforms. ^bCL/F reported. ^cFollowing a dose titration up to 200 mg given once daily for 30 days to healthy male (M) and female (F) adults.

References: van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet, 1993, 24:203–220. Warrington SJ. Clinical implications of the pharmacology of sertraline. Int Clin Psychopharmacol, 1994, 6(suppl 2):11–21.

Sildenafil^a

6.0 ± 1.1

↓ LD,^b RD,^c Aged

1.2 ± 0.3

2.4 ± 1.0

1.2 ± 0.3^d

212 ± 59 ng/mL^d

↑ Aged^d

^aData from healthy male subjects. Sildenafil is metabolized primarily by CYP3A and secondarily by CYP2C9. Piperazine N-desmethyl metabolite is active (~50% parent) and accumulates in plasma (~40% parent). ^bCL/F reduced, mild to moderate hepatic impairment. ^cCL/F reduced, severe renal impairment. Increased unbound concentrations. ^dFollowing a single50-mg oral (solution) dose.

References: PDR54, 2000, p. 2382. Walker DK, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica, 1999, 29:297–310.

Simvastatin^a

≤5

Negligible

7.6^b

—

2-3

AI: 1.4 ± 1.0^c

TI: 1.4 ± 1.0^c

AI: 46 ± 20 ngEq/mL^c

TI: 56 ± 25 ngEq/mL^c

^aSimvastatin is a lactone prodrug that is hydrolyzed to the active corresponding β-hydroxy acid. Values reported are for the disposition of the acid. ^bThe β-hydroxy acid can be reconverted back to the lactone; irreversible oxidative metabolites are generated by CYP3A. ^cData for active inhibitors (AI, ring-opened molecule) and total inhibitors (TI) following a 40-mg oral dose given once daily for 17 days to healthy adults.

References: Corsini A, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther, 1999, 84:413–428. Desager JP, et al. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet, 1996, 31:348–371. Mauro VF. Clinical pharmacokinetics and practicalapplications of simvastatin. Clin Pharmacokinet, 1993, 24:195–202.

Sirolimus^a

~15^b

↑ Food^b

—

40^c

3.47 ± 1.58^d

12 ± 4.6^d

62.3 ± 16.2^d

SD: 0.81 ± 0.17^e

MD: 1.4 ± 1.2^e

SD: 67 ± 23 ng/mL^e

MD: 94-210 ng/mL^e

^aData from male and female renal transplant patients. All subjects were on a stable cyclosporine regimen. Sirolimus is metabolized primarily by CYP3A and is a substrate for P-glycoprotein. Several sirolimus metabolites are pharmacologically active. ^bCyclosporine co-administration increases sirolimus bioavailability. F increased by high-fat meal. ^cConcentrates in blood cells; blood-to-plasma concentration ratio ~38 ± 13. ^dBlood CL/F, V_ss/F, and t_1/2 reported for oral dose. ^eFollowing a single 15-mg oral dose (SD) in healthy subjects and 4- to 6.5-mg/m² oral dose (with cyclosporine) given twice daily to steady state (MD) in renal transplant patients.

References: Kelly PA, et al. Conversion from liquid to solid rapamycin formulations in stable renal allograft transplant recipients. Biopharm Drug Dispos, 1999, 20:249–253. Zimmerman JJ, et al. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol, 1997, 37:405–415. Zimmerman JJ, et al. The effect of a high-fat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin).J Clin Pharmacol, 1999, 39:1155–1161.

Sitagliptin^a

87 ± 5.2

73.1 ± 15.9

4.42^b

↓ RD^c

↔ LD

–

13.9 ± 2.0

1.5 ± 1.3

1046 ± 286 nM^d

^aCleared primarily by the kidney. ^bRenal clearance is ~350 mL/min, which indicates active tubular secretion, possibly mediated by human Organic Anion Transporter-3 (OAT3) andP-glycoprotein (ABCB1). ^cApparent oral clearance increased by a respective 2.3-, 3.8- and 4.5-fold in patients with moderate (CL_cr = 30-50 mL/min) and severe (<30 mL/min) renal insufficiency and in patients with end-stage RD requiring hemodialysis. ^dFollowing a single 100-mg oral dose. Plasma AUC increased by ~14% following daily doses of 100 mg at steady state compared to the first dose.

References: Bergman A, et al. Absolute bioavailability of sitagliptin, an oral dipeptidylpeptidase-4 inhibitor, in healthy volunteers. Biopharm Drug Dispos, 2007, 28:315–22. Bergman AJ, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care, 2007, 30:1862–1864. Drugs@FDA. Januvia label approved on 7/22/08. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 26, 2009. Migoya EM, et al. Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. Can J Clin Pharmacol, 2009, 16:e165–e170. Vincent SH, et al. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [¹⁴C]sitagliptin in humans. Drug Metab Dispos, 2007, 35:533–538.

Solifenacin^a

3-6

98%^b

9.39 ± 2.68

↓ LD, RD^c

671 ± 118

52.4 ± 13.9

↓ LD, RD^c

4.2 ± 1.8^c

40.6 ± 8.5 ng/mL^d

^aSolifenacin is extensively metabolized by CYP3A. The 4R-hydroxy-solifenacin metabolite is pharmacologically active but not likely to contribute to the therapeutic efficacy of solifenacin because of low circulating levels. ^bPrimarily bound to α₁-acid glycoprotein. ^cDosage reduction is advised in patients with severe renal impairment (CL_cr <30 mL/min), in whom a 2-fold reduction in clearance and prolongation in t_1/2 are expected. ^dAt steady state following 21 days of dosing with 10 mg once daily.

References: Drugs@FDA. VESIcare label approved on 11/18/08. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 27, 2009. Kuipers M, et al. Open-label study of the safety and pharmacokinetics of solifenacin in subjects with hepatic impairment. J Pharmacol Sci, 2006, 102:405–412. Kuipers ME, et al. Solifenacin demonstrates high absolute bioavailability in healthy men. Drugs, 2004, 5:73–81. Smulders RA, et al. Pharmacokinetics and safety of solifenacin succinate in healthy young men. J Clin Pharmacol, 2004, 44:1023–1033. Smulders RA, et al. Pharmacokinetics, safety, and tolerability of solifenacin in patients with renal insufficiency. J Pharmacol Sci, 2007, 103:67–74.

Sorafenib^a

38-49^b

Negligible

99.5

1.2-2.0^c

↑ LD^d

20-27^c

2.0-12.1

5.4-10.0 μg/mL

^aSorafenib undergoes oxidative metabolism mediated by CYP3A and glucuronidation mediated by UGT1A9. ^bOral bioavailability of NEXAVAR tablet relative to an oral solution. Sorafenib bioavailability reduced by 29% when administered with a high-fat meal. ^cRange of geometric means determined at steady state in three phase I studies in patients with advanced refractory solid tumors at the dose level of 400 mg two times a day. ^dSorafenib AUCs were 23-63% lower in patients with mild and moderate hepatic impairment compared to patients with normal hepatic function.

References: Drugs@FDA. Nexavar label approved on 11-17-2007. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 27, 2009. Strumberg D, et al. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: A review of four phase I trials in patients with advanced refractory solid tumors. Oncologist, 2007, 12:426–437.

Sotalol^a

60-100

70 ± 15

Negligible

2.20 ± 0.67

↓ RD

1.21 ± 0.17

7.18 ± 1.30

↑ RD

3.1 ± 0.6

1.0 ± 0.5 μg/mL^b

^aSotalol is available as a racemate. The enantiomers contribute equally to sotalol's anti-arrhythmic action; hence, pharmacokinetic parameters for total enantiomeric mixture is reported herein. β-adrenoreceptor blockade resides solely with S-(–)-isomer. ^bFollowing80-mg, twice-a-day dosing to steady state.

References: Berglund G, et al. Pharmacokinetics of sotalol after chronic administration to patients with renal insufficiency. Eur J Clin Pharmacol, 1980, 18:321–326. Kimura M, et al. Pharmacokinetics and pharmacodynamics of (+)-sotalol in healthy male volunteers. Br J Clin Pharmacol, 1996, 42:583–588. Poirier JM, et al. The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers. Eur J Clin Pharmacol, 1990, 38:579–582.

Spironolactone^a

—^b

↑ Food

<1^c

>90^d

93^e

10^e

S: 1.3 ± 0.3^f

C: 11.2 ± 2.3^f

TS: 2.8 ± 0.4^f

HTS: 10.1 ± 2.3^f

↑ LD^g

S: 1.0^f

C: 2.9 ± 0.6^f

TS: 1.8 ± 0.5^f

HTS: 3.1 ± 0.9^f

S: 185 ± 51 ng/mL^f

C: 231 ± 49 ng/mL^f

TS: 571 ± 74 ng/mL^f

HTS: 202 ± 54 ng/mL^f

^aSpironolactone (S) is extensively metabolized; it has three known active metabolites: canrenone (C), 7α-thiomethylspironolactone (TS), and 6β-hydroxy-7α-thiomethylspironolactone (HTS). ^bAbsolute bioavailability is not known; old values reported in the literature were based on nonspecific assays for C; likely to exhibit first-pass metabolism. AUC of parent drug and metabolites increased when S taken with food. ^cMeasured after an oral dose. ^dBinding of S and its active metabolites. ^eCL/F and V_area/F; calculated from reported AUC and t_1/2 data. ^fFollowing a single 200-mg oral dose of S. C accumulates 2.5-fold with multiple S dosing. ^gt_1/2 of parent drug and metabolites increased in patients with cirrhosis.

References: Ho PC, et al. Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone. Eur J Clin Pharmacol, 1984, 27:441–446. Overdiek HW, et al. Influence of food on the bioavailability of spironolactone. Clin Pharmacol Ther, 1986, 40:531–536. Overdiek HW, et al. New insights into the pharmacokinetics of spironolactone. Clin Pharmacol Ther, 1985, 38:469–474. PDR54, 2000, p. 2883. Sungaila I, et al. Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites. Gastroenterology, 1992, 102:1680–1685.

Streptokinase^a

—

1.7 ± 0.7

0.08 ± 0.04^b

0.61 ± 0.24

0.9 ± 0.21^c

188 ± 58 IU/mL^c

^aValues obtained from acute MI patients using a function bioassay. ^bV_area reported. ^cFollowing a single 1.5 × 10⁶ IU IV dose given as a 60-minute infusion to patients with acute MI.

Reference: Gemmill JD, et al. A comparison of the pharmacokinetic properties of streptokinase and anistreplase in acute myocardial infarction. Br J Clin Pharmacol, 1991, 31:143–147.

Sulfamethoxazole

~100

14 ± 2

53 ± 5

↓ RD, Alb

↔ Aged, CF

0.31 ± 0.07^a,b

↔ RD

↑ CF

0.26 ± 0.04^a

↑ RD

↔ Child, CF

10.1 ± 2.6^a

↑ RD

↔ Child

↓ CF

4^b

37.1 μg/mL^b

^aStudies include concurrent administration of trimethoprim and variation in urinary pH; these factors had no marked effect on the CL of sulfamethoxazole. Metabolically cleared primarily by N₄-acetylation. ^bFollowing a single 1000-mg oral dose given to healthy adults.

References: Hutabarat RM, et al. Disposition of drugs in cystic fibrosis. I. Sulfamethoxazole and trimethoprim. Clin Pharmacol Ther, 1991, 49:402–409. Welling PO, et al. Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and in patients with renal failure. J Infect Dis, 1973, 128(suppl):556–566.

Sumatriptan

PO: 14 ± 5

SC: 97 ± 16

22 ± 4

14-21

22 ± 5.4

2.0 ± 0.34

1.0 ± 0.3^a

SC: 0.2 (0.1-0.3)^b

PO: ~1.5^b

SC: 72 (55-108) ng/mL^b

PO: 54 (27-137) ng/mL^b

^aAn apparent t_1/2 of ~2 hours reported for SC and oral doses. ^bFollowing a single 6-mg SC or 100-mg oral dose given to healthy young adults.

References: Scott AK. Sumatriptan clinical pharmacokinetics. Clin Pharmacokinet, 1994, 27:337–344. Scott AK, et al. Sumatriptan and cerebral perfusion in healthy volunteers. Br J Clin Pharmacol, 1992, 33:401–404.

Sunitinib^a

—^b

~9^c

P: 90

M: 95

7.3-14.8^d

4.0^d

40-60^e

P: 6.0 (0-8.3)

M: 6.0 (0-24)

P: 91.9 ± 42.3 ng/mL^f

M: 25.1 ± 11.0 ng/mL^f

^aSunitinib is metabolized primarily by CYP3A4 to produce its primary active metabolite (SU12662), which is further metabolized by CYP3A4. Plasma AUC of (SU12662) (M) is ~30% that of the parent drug (P) at steady state. ^bData on absolute oral bioavailability is not available. ^c16% of a radioactive dose of [¹⁴C]-sunitinib is recovered in urine, of which 86.4% is in the form of parent drug and active metabolite. ^dAverage CL/F of 34-62 L/hr and V_ss/F of 2230 L in 135 healthy volunteers and 266 patients with solid tumors, and assuming an average body weight of 77.6 kg. ^ePopulation estimate in 73 volunteers and 517 cancer patients. ^fSteady-state concentrations during once-daily dosing of 50 mg.

References: Britten CD, et al. A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol, 2008, 61:515–24. Drugs@FDA. Sutent label approved on 2/2/07. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 30, 2009. Houk BE, et al. A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients. Clin Cancer Res, 2009, 15:2497–2506.

Tacrolimus

25 ± 10^a,b

↔ RD

↓ Food

75-99^c

0.90 ± 0.29^a

↔ RD, LD

↑ LD

0.91 ± 0.29^a,d

↔ RD

12 ± 5^a

↔ RD

↑ LD

1.4 ± 0.5^e

31.2 ± 10.1 ng/mL^e

^aDrug disposition parameters calculated from blood concentrations. Data from liver transplant patients reported. Metabolized by CYP3A; also a substrate for P-glycoprotein. ^bA similar bioavailability (F = 21 ± 19%) reported for kidney transplant patients; F = 16 ± 7% for normal subjects. Low oral bioavailability likely due to incomplete intestinal availability. ^cDifferent values for plasma protein binding reported. Concentrates in blood cells; blood-to-plasma concentration ratio = 35 (12-67). ^dSlightly higher V_ss and t_1/2 reported for kidney transplant patients. Because of the very high and variable blood-to-plasma concentration ratio, markedly different V_ss values are reported for parameters based on plasma concentrations. ^eFollowing a single 7-mg oral dose given to healthy adults. Consensus target C_min at steady state are 5-20 ng/mL.

References: Bekersky I, et al. Dose linearity after oral administration of tacrolimus 1-mgcapsules at doses of 3, 7, and 10 mg. Clin Ther, 1999, 27:2058–2064. Jusko WJ, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther, 1995, 57:281–290. PDR54, 2000, pp. 1098–1099.

Tadalafil^a

—

0.59^b

↓ RD^c

0.89^b

17.5

2^d

378 ng/mL^d

^aEliminated primarily by CYP3A4-dependent metabolism. ^bCL/F and V/F reported. ^cAUC increased in patients with mild or moderate (2-fold) and severe (4-fold) renal insufficiency. ^dFollowing a single 20-mg oral dose.

References: Curran M, et al. Tadalafil. Drugs, 2003, 63:2203–2212; discussion 2213–2214. Product labeling: Cialis^® (tadalafil tablets). Bothell, WA, Lilly Icos, 2004.

Tamoxifen^a

—

>98

1.4^b,c

50-60^b

4-11 days^d

5 (3-7)

120 (67-183) ng/mL

^aHas active metabolites; 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen are minor metabolites that exhibit affinity for the estrogen receptor that is greater than that ofparent trans-tamoxifen. The t_1/2 of all metabolites are rate limited by tamoxifen elimination. ^bCL/F and V_area/F reported. ^cThe major pathway of elimination, N-demethylation, is catalyzed by CYP3A. ^dt_1/2 consistent with accumulation and approach to steady state. Significantly longer terminal t_1/2s are observed. ^eAverage C_ss following a 10-mg oral dose given twice daily to steady state.

References: L⊘nning PE, et al. Pharmacological and clinical profile of anastrozole. Breast Cancer Res Treat, 1998, 49(suppl 1):S53–S57. PDR54, 2000, p. 557.

Tamsulosin^a

100

↓ Food

12.7 ± 3.0

99 ± 1

↑ RD

0.62 ± 0.31

↑ RD,^b Aged

0.20 ± 0.06

6.8 ± 3.5^c

↑ RD, Aged

5.3 ± 0.7^d

↑ Food

16 ± 5 ng/mL^d

↑ Food

^aData from healthy male subjects. Metabolized primarily by CYP3A and CYP2D6. ^bCL/F reduced, moderate renal impairment. Unbound AUC relatively unchanged. ^cApparent t_1/2 after oral dose in patients is ~14-15 hours, reflecting controlled release from modified-release granules. ^dFollowing a single 0.4-mg modified-release oral dose in healthy subjects.

References: Matsushima H, et al. Plasma protein binding of tamsulosin hydrochloride in renal disease: Role of α₁-acid glycoprotein and possibility of binding interactions. Eur J Clin Pharmacol, 1999, 55:437–443. van Hoogdalem EJ, et al. Disposition of the selective α_1A-adrenoceptor antagonist tamsulosin in humans: Comparison with data from interspecies scaling. J Pharm Sci, 1997, 86:1156–1161. Wolzt M, et al. Pharmacokinetics of tamsulosin in subjects with normal and varying degrees of impaired renal function: An open-label single-dose and multiple-dose study. Eur J Clin Pharmacol, 1998, 4:367–373.

Telithromycin^a

57 (41-112)

23 (19-27)

14 (12-16)

↓ RD^b

3.0 (2.1-4.5)

12 (7-23)

1.0 (0.5-3.0)^c

2.23 μg/mL^c

^a~35% of the dose is metabolized by CYP3A4. ^bCL/F reduced in patients with severe renal impairment. ^cFollowing an 800-mg oral dose given once daily for 7 days.

References: Ferret C, et al. Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of telithromycin in healthy young and elderly volunteers. Chemotherapy, 2002, 48:217–223. Namour F, et al. Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administered in ascending single and multiple doses. Antimicrob Agents Chemother, 2001, 45:170–175. Zhanel GG, et al. The ketolides: A critical review. Drugs, 2002, 62:1771–1804.

Temsirolimus^a

—

4.6^b

—^c

3.8 ± 0.6^d

3.3 ± 0.5^d

12.8 ± 1.1

—

595 ± 102 ng/mL^e

^aTemsirolimus, a water-soluble ester analog of sirolimus or rapamycin, is available for IV use. Following IV administration, temsirolimus is converted to sirolimus; blood AUC of sirolimus is 3-fold higher than that of temsirolimus at the recommended dose of 25 mg for the treatment of advanced renal cell carcinoma. Both temsirolimus and sirolimus inhibit mTOR kinase activity and undergo oxidative metabolism mediated by CYP3A. ^bRecovery of radioactivity after a single IV dose of [¹⁴C]-temsirolimus. ^cBoth temsirolimus and sirolimus partition extensively into blood cells; a major fraction of temsirolimus and sirolimus in plasma is bound to plasma proteins. ^dBased on CL of 16.1 ± 2.5 L/hr and V_ss of 232 ± 36 l at a dose of 25 mg, assuming an average body weight of 70 kg. All pharmacokinetic assessments are based on whole blood concentration. ^eFollowing the first dose of a 25-mg/wk regimen.

References: Atkins MB, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol, 2004, 22:909–918. Drugs@FDA. Torisel label approved on 5/30/07. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 31, 2010.

Tenofovir^a

25^b

↑ Food

82 ± 13

2.6 ± 0.9^c

↓ RD

0.6 ± 0.1^c

8.1 ± 1.8^c,d

↑ RD

2.3^e

326 ng/mL^e

^aTenofovir is formulated as an ester prodrug, VIREAD (tenofovir disoproxil fumarate), for oral administration. ^bBioavailability under fasted state reported; increased to 39% with high-fat meal. ^cData reported for steady-state 3-mg/kg IV dose given once a day for 2 weeks to HIV-1-infected male and female adults. Slightly higher CL with single IV dose. ^dLonger apparent plasma t_1/2 (17 hours) reported for steady-state oral dosing; this may reflect a longer duration of blood sampling; also, phosphorylated "active" metabolite exhibits a longer intracellulart_1/2 (60 hours). ^eFollowing a 300-mg oral dose given once a day with a meal to steady state.

References: Barditch-Crovo P, et al. Phase i/ii trial of the pharmacokinetics, safety, andantiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother, 2001, 45:2733–2739. Deeks SG, et al. Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(Phosphonomethoxy) propyl]adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults. Antimicrob Agents Chemother, 1998, 42:2380–2384. Kearney BP, et al. Tenofovir disoproxil fumarate: Clinical pharmacology and pharmacokinetics. Clin Pharmacokinet, 2004, 43:595–612.

Terazosin

11-14

90-94

1.1-1.2^a

1.1

9-12

1.7^b

16 ng/mL^b

^aPlasma CL reportedly reduced in patients with hypertension. ^bFollowing a 1-mg oral dose (tablet) given to healthy volunteers.

References: Senders RC. Pharmacokinetics of terazosin. Am J Med, 1986, 80:20–24. Sennello LT, et al. Effect of age on the pharmacokinetics of orally and intravenously administered terazosin. Clin Ther, 1988, 10:600–607.

Thalidomide^a

—^b

—

2.2 ± 0.4^c

1.1 ± 0.3^c

6.2 ± 2.6^c

3.2 ± 1.4^d

↑ HD, Food

2.0 ± 0.6 μg/mL^d

↑ HD

^aData from healthy male subjects. Similar data reported for asymptomatic patients with HIV. No age or gender differences. Thalidomide undergoes spontaneous hydrolysis in blood to multiple metabolites. ^bAbsolute bioavailability is not known. Altered absorption rate and extent, Hansen's disease (HD). ^cCL/F, V_area/F, and t_1/2 reported for oral dose. ^dFollowing asingle 200-mg oral dose.

References: Noormohamed FH, et al. Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects. AIDS Res Hum Retrovir, 1999, 15:1047–1052. PDR54, 2000, p. 912. Teo SK, et al. Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.J Clin Pharmacol, 1999, 39:1162–1168.

Tigecycline^a

—

22^b

71-89

3.3 ± 0.3^c

7.2 ± 0.5^c

36.9 ± 11.8^c

—

621 ± 93 ng/mL^c

^aTigecycline is a glycylcycline, a new tetracycline class of antibiotic. Tigecycline undergoes minimal metabolism; major routes of elimination are via biliary and urinary excretion. ^bPercent of dose excreted as unchanged drug in urine. ^cAt steady state during repetitive 50-mg IV doses of tigecycline infused over a 1-hour period given every 12 hours.

References: Drugs@FDA. Tygacil label approved on 3/20/09. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 31, 2009. Muralidharan G, et al. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother, 2005, 49:220–229.

Tolterodine^a

EM: 26 ± 18

PM: 91 ± 40

EM: ↑ Food

EM: Negligible

PM: <2.5

T: 96.3

5-HM: 64

EM: 9.6 ± 2.8

PM: 2.0 ± 0.3

↓ LD^b

EM: 1.7 ± 0.4

PM: 1.5 ± 0.4

EM: 2.3 ± 0.3

PM: 9.2 ± 1.2

↑ LD

EM: 1.2 ± 0.5^c

PM: 1.9 ± 1.0^c

EM: 5.2 ± 5.7 ng/mL^c

PM: 38 ± 15 ng/mL^c

^aData from healthy adult male subjects. No significant gender differences. Tolterodine (T) is metabolized primarily by CYP2D6 to an active (100% potency) metabolite, 5-hydroxymethyl tolterodine (5-HM), in extensive metabolizers (EM); t_1/2 5-HM = 2.9 ± 0.4 hour. Also metabolized by CYP3A to an N-desalkyl product, particularly in poor metabolizers (PM). ^bCL/F reduced and AUC 5-HM_unbound increased, hepatic cirrhosis. ^cFollowing a 4-mg oral dose given twice daily for 8 days. C_max of 5-HM was 5 ± 3 ng/mL for EM.

References: Brynne N, et al. Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamic of tolterodine. Clin Pharmacol Ther, 1998, 63:529–539. Hills CJ, et al. Tolterodine. Drugs, 1998, 55:813–820. PDR54, 2000, p. 2439.

Topiramate^a

>70^b

70-97

13-17

0.31-0.51^c

↑ Child^d

↓ RD^e

0.6-0.8^c

19-23^c

↑ RD

1.7 ± 0.6^f

5.5 ± 0.6 μg/mL^f

^aData from healthy adult male and female subjects and patients with partial epilepsy. ^bEstimate of bioavailability based on urine recovery of unchanged drug. ^cCL/F, V_area/F, and t_1/2 reported for oral dose. Patients receiving concomitant therapy with enzyme-inducing anticonvulsant drugs exhibit increased CL/F and decreased t_1/2. ^dCL/F increased, <4 years of age (substantially), and 4-17 years of age. ^eCL/F reduced, moderate-to-severe renal impairment (drug cleared by hemodialysis). ^fFollowing a 400-mg oral dose given twice daily to steady state in patients with epilepsy.

References: Glauser TA, et al. Topiramate pharmacokinetics in infants. Epilepsia, 1999, 40:788–791. PDR54, 2000, p. 2209. Rosenfeld WE. Topiramate: A review of preclinical, pharmacokinetic, and clinical data. Clin Ther, 1997, 19:1294–1308. Sachdeo RC, et al. Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsyduring monotherapy and concomitant therapy. Epilepsia, 1996, 37:774–780.

Toremifene^a

—

Negligible

99.7

2.6 ± 1.2 L/hr/m^{2 b}

↓ LD,^c RD

479 ± 154 L/m^{2 b}

↑ Aged

T: 148 ± 53^b

DMT: 504 ± 578^b

↑ Aged, LD

T: 1.5-3^d

DMT: 3-6^d

T: 1.1-1.3 μg/mL^d

DMT: 2.7-5.8 μg/mL^d

^aData from healthy adult male and female subjects and female patients with breast cancer. Toremifene (T) is metabolized by CYP3A to N-desmethyltoremifene (DMT), a metabolite that accumulates in blood and has anti-estrogenic activity. Toremifene appears to undergo enterohepatic recycling, prolonging its apparent t_1/2. ^bCL/F, V_area/F, and t_1/2 reported for oral dose. ^cCL/F reduced, hepatic cirrhosis or fibrosis. ^dFollowing a 60-mg oral dose given once daily to steady state in patients with breast cancer.

References: Anttila M, et al. Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function. Clin Pharmacol Ther, 1995, 57:628–635. Bishop J, et al. Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal patients with advanced breast cancer. Cancer Chemother Pharmacol, 1992, 30:174–178. Wiebe VJ, et al. Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer. Cancer Chemother Pharmacol, 1990, 25:247–251.

Tramadol^a

70-75

10-30^b

8 (6-12)

↓ LD, RD

2.7 (2.3-3.9)

5.5 (4.5-7.5)

↑ RD, LD

T: 2.3 ± 1.4^c

Ml: 2.4 ± 1.1^c

T: 592 ± 178 ng/mL^c

Ml: 110 ± 32 ng/mL^c

^aTramadol (T) is available as a racemic mixture. At steady state, the plasma concentration of (+) (1R,2R)-tramadol is ~30% higher than that of (−) (1S,2S)-tramadol. Both isomers contribute to analgesia. Data reported are for total (+ and −) T. T is metabolized by CYP2D6 to an active O-desmethyl metabolite (M1); there are other CYP-catalyzed metabolites. ^bRecovery following an oral dose was reported. ^cFollowing a 100-mg immediate-release tablet given every 6 hours for 7 days.

References: Klotz U. Tramadol—The impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain. Arzneimittelforschung, 2003, 53:681–687. PDR58, 2004, p. 2494.

Trazodone^a

81 ± 6

↔ Aged, Obes

2.1 ± 0.1

↓ Aged,^b Obes^c

1.0 ± 0.1^d

↑ Aged, Obes

5.9 ± 0.4

↑ Aged, Obes

2.0 ± 1.5^e

1.5 ± 0.2 μg/mL^e

^aActive metabolite, m-chlorophenylpiperazine, is a tryptaminergic agonist; formation catalyzed by CYP3A. ^bSignificant for male subjects only. ^cNo difference when CL is normalized to ideal body weight. ^dV_area reported. ^eFollowing a single 100-mg oral dose (capsule) given with a standard breakfast to healthy adults.

References: Greenblatt DJ, et al. Trazodone kinetics: Effect of age, gender, and obesity. Clin Pharmacol Ther, 1987, 42:193–200. Nilsen OG, et al. Single dose pharmacokinetics of trazodone in healthy subjects. Pharmacol Toxicol, 1992, 71:150–153.

Triamterene^a

51 ± 18^b

52 ± 10^b

↓ LD^c

↔ Aged^b

61 ± 2^d

↑ HL

↓ RD, Alb, LD^e

63 ± 20^f

↓ LD, RD,^e Aged^e

13.4 ± 4.9

4.2 ± 0.7^g

↑ RD^e

T: 2.9 ± 1.6^h

TS: 4.1 ± 2.0^h

Y, T: 26.4 ± 17.7 ng/mL^h

Y, TS: 779 ± 310 ng/mL^h

E, T: 84 ± 91 ng/mL^h

E, TS: 526 ± 388 ng/mL^h

^aActive metabolite, hydroxytriamterene sulfuric acid ester (TS). ^bTriamterene (T) plus active metabolite. ^cDecreased active metabolite; increased parent drug. ^dFor metabolite, percent bound = 90.4 ± 1.3. ^eActive metabolite. ^fBecause T is predominantly present in plasma as the active metabolite, this value is deceptively high. CL_renal = 2.3 ± 0.6 for the metabolite. ^gMetabolite t_1/2 = 3.1 ± 1.2 hours. ^hData for T and TS following a single 50-mg oral dose taken after a fast by young healthy volunteers (Y) and elderly patients requiring diuretic therapy (E).

References: Gilfrich HJ, et al. Pharmacokinetics of triamterene after i.v. administration to man: Determination of bioavailability. Eur J Clin Pharmacol, 1983, 25:237–241. Muhlberg W, et al. Pharmacokinetics of triamterene in geriatric patients—Influence of piretanide and hydrochlorothiazide. Arch Gerontol Geriatr, 1989, 8:73–85.

Trimethoprim

>63

63 ± 10

↔ CF

37 ± 5

↔ RD, Alb, CF

1.9 ± 0.3^a

↓ RD

↑ CF, Child

1.6 ± 0.2^a

↔ RD, CF

↑ Neo, Child

10 ± 2^a

↑ RD

↓ Child, CF

2^b

1.2 μg/mL^b

^aStudies included concurrent administration of sulfamethoxazole and variation in urinary pH; these factors had no marked effect on the CL, V_area, and t_1/2 of trimethoprim. ^bFollowing a single 160-mg oral dose given to healthy adults.

References: Hutabarat RM, et al. Disposition of drugs in cystic fibrosis. I. Sulfamethoxazole and trimethoprim. Clin Pharmacol Ther, 1991, 49:402–409. Welling PO, et al. Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and inpatients with renal failure. J Infect Dis, 1973, 128(suppl):556–566.

Valacyclovir^a

V: very low

A: 54 (42-73)^b

V: <1

A: 44 ± 10^c

V: 13.5-17.9

A: 22-33

V: —

A: ↓ RD^d

—

V: —

A: 2.5 ± 0.3

A: ↑ RD

V: 1.5

A: 1.9 ± 0.6^e

V: ≤0.56 μg/mL^e

A: 4.8 ± 1.5 μg/mL^e

^aData from healthy male and female adults. Valacyclovir is an L-valine prodrug of acyclovir. Extensive first-pass conversion by intestinal (gut wall and luminal) and hepatic enzymes. Parameters refer to acyclovir (A) and valacyclovir (V) following V administration. See "Acyclovir" for its systemic disposition parameters. ^bBioavailability of A based on AUC of A following IV A and a 1-g oral dose of V. ^cUrinary recovery of A is dose dependent (76% and 44% following 100-mg and 1000-mg oral doses of V, and 87% following IV A). ^dCL/F reduced, end-stage RD (drug cleared by hemodialysis). ^eFollowing a single 1-g oral dose of V.

References: Perry CM, et al. Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs, 1996, 52:754–772. Soul-Lawton J, et al. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother, 1995, 39:2759–2764. Weller S, et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther, 1993, 54:595–605.

Valganciclovir^a

G (V): 61 ± 9^b

↑ Food

—

V (V): 0.5 ± 0.2

G (V): 3.7 ± 0.6

↑ RD^c

V (V): 0.5 ± 0.3^d

G (V): l-3^e

V (V): 0.20 ± 0.07 μg/mL^d

G (V): 5.6 ± 1.5 μg/mL^e

^aValganciclovir (V) is an ester prodrug for ganciclovir (G). It is rapidly hydrolyzed with a plasma t_1/2 = 0.5 hour. G and V data following oral V dosing to male and female patients with viral infections are reported. See "Ganciclovir" for its systemic disposition parameters. ^blncreased and more predictable bioavailability of G when V is taken with a high-fat meal. ^cThe apparent t_1/2 of G is increased in patients with renal impairment. ^dFollowing a single 360-mg oral dose of V taken without food. ^eFollowing a 900-mg oral dose of V taken once daily with food to steady state.

References: Cocohoba JM, et al. Valganciclovir: An advance in cytomegalovirus therapeutics. Ann Pharmacother, 2002, 36:1075–1079. Jung D, et al. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J Clin Pharmacol, 1999, 39:800–804. PDR58, 2004, pp. 2895, 2971.

Valproic Acid^a

100 ± 10^b

1.8 ± 2.4

93 ± l^c

↓ RD, LD, Preg, Aged, Neo, Burn, Alb

0.11 ± 0.02^d,e

↑ Child

↔ LD, Aged

0.22 ± 0.07

↑ LD, Neo

↔ Aged, Child

14 ± 3^d,e

↑ LD, Neo

↓ Child

↔ Aged

l-4^f

34 ± 8 μg/mL^f

^aValproic acid is available either as the free acid or stable coordination compound comprised of sodium valproate and valproic acid (divalproex sodium). ^bSystemic availability of valproate ion is the same after molar equivalent oral doses of free acid and divalproex sodium. ^cDose dependent; value shown for daily doses of 250 and 500 mg. At 1 g daily, percent bound = 90 ± 2%. ^dData for multiple dosing (500 mg daily) reported. Single-dose value: 0.14 ± 0.04 mL/min/kg; t_1/2 = 9.8 ± 2.6 hours. Total CL is the same at 100 mg daily, although CL of free drug increases with multiple dosing. ^eIncreased CL and decreased t_1/2 from enzyme induction following concomitant administration of other anti-epileptic drugs. ^faverage concentration following a 250-mg oral dose (capsule, DEPAKENE) given twice daily for 15 days to healthy male adults. A therapeutic range of 50-150 μg/mL is reported. T_max is 3-8 hours for divalproex tablets and 7-14 hours for extended-release divalproex tablets.

References: Dean JC. Valproate. In: Wyllie E, ed. The Treatment of Epilepsy, 2nd ed. Baltimore, Williams & Wilkins, 1997, pp. 824–832. Pollack GM, et al. Accumulation and washout kinetics of valproic acid and its active metabolites. J Clin Pharmacol, 1986, 26:668–676. Zaccara G, et al. Clinical pharmacokinetics of valproic acid—1988. Clin Pharmacokinet, 1988, 15:367–389.

Valsartan^a

23 ± 7

↓ Food

29.0 ± 5.8

0.49 ± 0.09

↓ Aged, LD^b

↔ RD

0.23 ± 0.09

9.4 ± 3.8

↑ Aged

2 (1.5-3)^c

1.6 ± 0.6 μg/mL^c

^aData from healthy adult male subjects. No significant gender differences. Valsartan is cleared primarily by biliary excretion. ^bCL/F reduced, mild to moderate hepatic impairment and biliary obstruction. ^cFollowing a single 80-mg oral dose (capsule).

References: Brookman LJ, et al. Pharmacokinetics of valsartan in patients with liver disease. Clin Pharmacol Ther, 1997, 62:272–278. Flesch G, et al. Absolute bioavailability andpharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol, 1997, 52:115–120. Muller P, et al. Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensivesubjects. Eur J Clin Pharmacol, 1997, 52:441–449. PDR54, 2000, p. 2015.

Vancomycin

—^a

79 ± 11

30 ± 11

↔ RD

CL = 0.79CL_cr + 0.22

↓ RD, Aged, Neo

↔ Obes, CPBS

↑ Burn

0.39 ± 0.06

↓ Obes

↔ RD, CPBS

5.6 ± 1.8

↑ RD, Aged

↓ Obes

—

18.5 (15-25) μg/mL^b

^aVery poorly absorbed after oral administration, but used by this route to treat Clostridium difficile and staphylococcal enterocolitis. ^bFollowing a dose of 1000-mg IV (1-hour infusion) given twice daily or a 7.5-mg/kg IV (1-hour infusion) given four times daily to adult patients with staphylococcal or streptococcal infections. Levels of 37-152 μg/mL have been associated with ototoxicity.

Reference: Leader WG, et al. Pharmacokinetic optimisation of vancomycin therapy. Clin Pharmacokinet, 1995, 28:327–342.

Vardenafil^a

15 (8-25)

2-6

93-95 (parent and M1)

3.0^b

4-5 (parent and M1)

0.7 (0.25-3)^c

19.3 ± 1.7 ng/mL^c

^aVardenafil is primarily metabolized by CYP3A with minor involvement of CYP2C9. The major oxidative metabolite (M1), a product of N-desmethylation at the piperazine ring, is a less potent PDE5 inhibitor and circulates at a level 28% that of the parent drug. It contributes only 7% of the in vivo activity of vardenafil. ^bV_ss of 208 L, assuming 70-kg bodyweight. ^cFollowing a single 20-mg dose. There is no change in pharmacokinetics between single and multiple dosing.

References: Drugs@FDA. Levitra label approved on 3/19/08. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 31, 2009. Gupta M, et al. The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction. J Clin Pharmacol, 2005, 45:987–1003.

Varenicline^a

≥87%^b

86.2 ± 6.2

≤20

2.27 ± 0.34^c

6.2^c

31.5 ± 7.7^c

2.0 (1.0-4.0)^d

10.2 ± 1.0 ng/mL^d

^aVarenicline is eliminated mostly by renal excretion with minimal metabolism. Organic Cation Transporter 2 (OCT2) is involved in renal tubular secretion, as evidenced by inhibition of varenicline renal clearance by cimetidine, a known OCT2 inhibitor. ^b87.1 ± 5.5% of radioactivity is excreted in urine after an oral dose of [¹⁴C]-varenicline. Minimal first-pass metabolism is expected. ^cCL/F and V_z/F estimated from steady-state AUC and t_1/2 during 1-mg twice-daily dosing of varenicline in healthy adult smokers and assuming an average body weight of 70 kg. ^dAfter the first dose of a multiple-dosing regimen. An accumulation factor of 2.85 ± 0.73 was reported.

References: Drugs@FDA. Chantix label approved on 7/1/09. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on December 31, 2009. Faessel HM, et al. Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers. J Clin Pharmacol, 2006, 46:1439–1448. Obach RS, et al. Metabolism and disposition of varenicline, a selective α4β2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos, 2006, 34:121–130.

Venlafaxine,^a Desvenlafaxine^b

10-45

V: 4.6 ± 3.0

ODV: 29 ± 7^c

V: 27 ± 2

ODV: 30 ± 12^c

22 ± 10^d

↔ Aged, Fem

↓ LD, RD

7.5 ± 3.7^d

↔ Aged, Fem,

LD, RD

4.9 ± 2.4

10.3 ± 4.3^c

↔ Aged, Fem

↑ LD, RD

V: 2.0 ± 0.4

ODV: 2.8 ± 0.8^c

V: 167 ± 55 ng/mL^e

ODV: 397 ± 81 ng/mL^e

^aVenlafaxine (V) is available as a racemic mixture; antidepressant activity resides with thel-(–)-enantiomer and its equipotent O-desmethyl metabolite (formation catalyzed by CYP2D6—polymorphic). Parameters for the derived O-desmethylvenlafaxine (ODV) are included. ^bO-Desmethyl metabolite is marketed as desvenlafaxine in an extended-releaseformulation as a successor to V. It has a higher oral bioavailability (80%), with a T_max of 7.5 hours. Desvenlafaxine has a much lower CL (3.5 mL/min/kg) and a smaller V_ss (3.4 L/kg). Its reported t_1/2 matches that observed for metabolite derived from V. ^cValues for ODV afterV dosing. ^dCL/F and V_ss/F reported. ^eMean data for V and ODV, following a 75-mg oral dose (immediate-release tablet) given three times daily for 3 days to healthy adults. T_max for an extended-release formulation is 5.5 (V) and 9 (DV) hours.

References: Klamerus KJ, et al. Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite. J Clin Pharmacol, 1992, 32:716–724. PDR54, 2000, p. 3237.

Verapamil^a,b

Oral: 22 ± 8

SL: 35 ± 13

↑ Cirr

↔ RD

90 ± 2

↑ Cirr

↔ RD, Atr

Fib, Aged

15 ± 6^c,d

↑ Cirr, Aged, Obes

↑, ↔ Atr Fib

↔ RD, Child

5.0 ± 2.1

↑ Cirr

↑, ↔ Atr Fib

↔ RD, Aged, Obes

4.0 ± 1.5^c

↑ Cirr, Aged, Obes

↑, ↔ Atr Fib

↔ RD, Child

IR: 1.1^e

XR: 5.6-7.7^e

IR: 272 ng/mL^e

XR: 118-165 ng/mL^e

^aRacemic mixture; (–)-enantiomer is more active. Bioavailability of (+)-verapamil is 2.5-fold greater than that for (–)-verapamil because of a lower CL (10 ± 2 versus 18 ± 3 mL/min/kg). Relative concentration of the enantiomers changes as a function of route of administration. ^bActive metabolite, norverapamil, is a vasodilator but has no direct effect on heart rate or P-R interval. At steady state (oral dosing), AUC is equivalent to that of parent drug (t_1/2 = 9 ± 3 hours). ^cMultiple dosing causes a greater than 2-fold decrease in CL/F and prolongation of t_1/2 in some studies, but no change of t_1/2 in others. ^dVerapamil is a substrate for CYP3A4, CYP2C9, and other CYPs. ^eMean data following a 120-mg oral conventional tablet (IR) given twice daily or range of data following a 240-mg oral extended-release (XR) dose given once daily, both for 7-10 days to healthy adults. EC₅₀ for prolongation of P-R interval after an oral dose of racemate is 120 ± 20 ng/mL; the value for IV administration is 40 ± 25 ng/mL. After oral administration, racemate concentrations >100 ng/mL cause >25% reduction in heart rate in Atr Fib, >10% prolongation of P-R interval, and >50% increase in duration of exercise in angina patients. A level of 120 ± 40 ng/mL (after IV administration) was found to terminate reentrant supraventricular tachycardias.

Reference: McTavish D, et al. Verapamil. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs, 1989, 38:19–76.

Vincristine^a

—

10-20

Low

4.92 ± 3.01 L/hr/m²

↔ Child

96.9 ± 55.7 L/m^{2 c}

↑ LD^b

22.6 ± 16.7^c

—

~250-425 nM^d

^aData from adult male and female cancer patients. Metabolized by CYP3A and excreted unchanged into bile (substrate for P-glycoprotein). ^bCL reduced, cholestatic liver disease.^ct_1/2 and V_z for terminal phase. Longer t_1/2 (~85 ± 69 hours) also reported. ^dFollowing a 2-mg IV bolus dose.

References: Gelmon KA, et al. Phase I study of liposomal vincristine. J Clin Oncol, 1999, 17:697–705. Rahmani R, et al. Pharmacokinetics and metabolism of vinca alkaloids. Cancer Surv, 1993, 17:269–281. Sethi VS, et al. Pharmacokinetics of vincristine sulfate in adult cancer patients. Cancer Res, 1981, 41:3551–3555. Sethi VS, et al. Pharmacokinetics of vincristine sulfate in children. Cancer Chemother Pharmacol, 1981, 6:111–115. van den Berg HW, et al. The pharmacokinetics of vincristine in man: Reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol, 1982, 8:215–219.

Vinorelbine

27 ± 12^a

87 (80-91)

21 ± 7

↓ LD

76 ± 41^b

42 ± 21^b

1.5 ± 1.0^c

114 ± 43 ng/mL^c

1130 ± 636 ng/mL^d

^aFor liquid-filled gelatin capsules. ^bElimination kinetics of vinorelbine follow a three-compartment model with extensive tissue distribution. Values for the terminal elimination phase are reported. ^cFollowing a single 100-mg/m² oral dose (gel capsule). ^dFollowing a single 30-mg/g IV infusion over 15 minutes.

Reference: Leveque D, et al. Clinical pharmacokinetics of vinorelbine. Clin Pharmacokinet, 1996, 37:184–197.

Voriconazole^a

↓ Food

3.8^b

↓ LD^c

1.6^b

6.7^b

PO: 1.1^d

↑ Food

PO: 2356 ng/mL^d

↓ Food

IV: 3621 ng/mL^e

^aMetabolized mainly to an inactive N-oxide by CYP2C19 (major), CYP3A4, and CYP2C9. ^bElimination is dose and time dependent. Pharmacokinetic parameters determined at steady state are reported. Mean CL was reduced (64%), V_ss reduced (32%), and t_1/2 increased (16%) with 12 days of twice-daily 3-mg/kg IV administration. Also, CL decreased 41% when dose was increased from 200-300 mg twice daily. ^cCL reduced in patients with mild to moderate hepatic insufficiency. ^dFollowing a 3-mg/kg oral dose given twice daily for 12 days. ^eFollowing a 3-mg/kg IV infusion over 1-hour given twice daily for 12 days.

References: Boucher HW, et al. Newer systemic antifungal agents: Pharmacokinetics, safety and efficacy. Drugs, 2004, 64:1997–2020. Purkins L, et al. The pharmacokinetics and safety of intravenous voriconazole—A novel wide-spectrum antifungal agent. Br J Clin Pharmacol, 2003, 56(suppl):2–9. Purkins L, et al. Voriconazole, a novel wide-spectrum triazole: Oral pharmacokinetics and safety. Br J Clin Pharmacol, 2003, 56(suppl):10–16.

Warfarin^a

93 ± 8

99 ± l^b

↓ RD

↔ Preg

0.045 ± 0.024^c,d,e

↔ Aged, AVH, CF

0.14 ± 0.06^b,d

↔ Aged, AVH

37 ± 15^f

↔ Aged, AVH

<4^g

R: 0.9 ± 0.4 μg/mL^g

S: 0.5 ± 0.2 μg/mL^g

^aValues are for racemic warfarin; the S-(–)-enantiomer is 3- to 5-fold more potent than the R-(+)-enantiomer. ^bNo difference between enantiomers in plasma protein binding or V_area. ^cCL of the R-enantiomer is ~70% of that of the antipode (0.043 versus 0.059 mL · min^{− 1} · kg⁻¹). ^dConditions leading to decreased binding (e.g., uremia) presumably increase CL and V. ^eThe S-enantiomer is metabolically cleared by CYP2C9 (polymorphic). ^ft_1/2 of the R-enantiomer is longer than that of the S-enantiomer (43 ± 14 versus 32 ± 12 hours). ^gMean steady-state, 12-hour postdose concentrations of warfarin enantiomers following a daily oral dose of 6.1 ± 2.3 mg of racemic warfarin given to patients with stabilized (1-5 months) anticoagulant therapy.

Reference: Chan E, et al. Disposition of warfarin enantiomers and metabolites in patientsduring multiple dosing with rac-warfarin. Br J Clin Pharmacol, 1994, 37:563–569.

Zidovudine

63 ± 10

↑ Neo

↔ Preg

18 ± 5

<25

26 ± 6^a

↓ RD,^b Neo, LD

↔ Child, Preg

1.4 ± 0.4

↓ RD,^b LD

↔ Child, Preg

1.1 ± 0.2

↔ RD, Preg

↑ Neo, LD

0.5-l^c

IV: 2.6 μg/mL^c

PO: 1.6 μg/mL^c

^aFormation of 5-O-glucuronide is the major route of elimination (68%). ^bA change in CL/F and V_area/F reported. ^cFollowing a 5-mg/kg IV or oral dose given every 4 hours to steady state.

References: Blum MR, et al. Pharmacokinetics and bioavailability of zidovudine in humans. Am J Med, 1988, 85:189–194. Morse GD, et al. Comparative pharmacokinetics of antiviral nucleoside analogues. Clin Pharmacokinet, 1993, 24:101–123.

Ziprasidone^a

PO: 59

↑ Food

IM: 100

<l^b

99.9 ± 0.08

11.7

2.3

2.9^c

PO: 4 ± l^d

IM: 0.7^e

PO: 68 ± 20 ng/mL^d

IM: 156 ng/mL^e

^aApproximately one-third of the dose is oxidized by CYP3A4, and the remainder undergoes reduction. ^bRecovery following oral administration. ^cA longer t_1/2 after oral dosing is rate limited by absorption; food decreases apparent t_1/2. In the elderly, the t_1/2 is slightly longer. ^dFollowing a 20-mg oral dose given twice daily for 8 days. ^eFollowing a single 10-mg IM dose.

References: Gunasekara NS, et al. Ziprasidone: A review of its use in schizophrenia and schizoaffective disorder. Drugs, 2002, 62:1217–1251. Miceli JJ, et al. Single- and multiple-dose pharmacokinetics of ziprasidone under nonfasting conditions in healthy male volunteers. Br J Clin Pharmacol, 2000, 49(suppl):5S–13S. PDR58, 2004, p. 2598. Wilner KD, et al. Single- and multiple-dose pharmacokinetics of ziprasidone in healthy young and elderlyvolunteers. Br J Clin Pharmacol, 2000, 49(suppl):15S–20S.

Zolpidem

72 ± 7

↑ RD, LD

4.5 ± 0.7^a

↔ RD

↓ LD, Aged

↑ Child

0.68 ± 0.06

↑ RD

1.9 ± 0.2

↑ Aged, LD

↔ RD

↓ Child

1.0-2.6^b

↑ Food

76-139 ng/mL^b

↓ Food

^aMetabolically cleared predominantly by CYP3A4. ^bFollowing a single 10-mg oral dose given to young adults. No accumulation of drug with once-daily dosing.

References: Greenblatt DJ, et al. Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pharmacol Ther, 1998, 64:553–561. Patat A, et al. EEG profile ofintravenous zolpidem in healthy volunteers. Psychopharmacology (Berl), 1994, 114:138–146. Salva P, et al. Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. Clin Pharmacokinet, 1995, 29:142–153.

Zonisamide^a

—^b

29-48^c

38-40^d

0.13^e

1.2-1.8^f

63 ± 14

1.8 ± 0.4^g

28 ± 4 μg/mL^g

^aPrimary routes of metabolism involve reductive cleavage of the isoxazole ring (CYP3A4) and N-acetylation. ^bAbsolute bioavailability is not known; minimum equal to urine recovery after an oral dose. ^cRecovery following an oral dose. ^dConcentrates in erythrocytes to as much as 8-fold. ^eSteady-state CL/F for a 400-mg once-daily dose reported. AUC increases disproportionately when the dose is increased from 400-800 mg. ^fV/F for a single dose is reported; decreases as the dose is increased from 200-800 mg. ^gFollowing a 400-mg oral dose given once daily to steady state in healthy adults.

References: Kochak GM, et al. Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures. J Clin Pharmacol, 1998, 38:166–171. Peters DH, et al. Zonisamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs, 1993, 45:760–787. PDR58, 2004, p. 1232.

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Appendix II: Design and Optimization of Dosage Regimens: Pharmacokinetic Data

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INTRODUCTION

TABULATED PHARMACOKINETIC PARAMETERS

ALTERATIONS OF PARAMETERSIN THE INDIVIDUAL PATIENT

INDIVIDUALIZATION OF DOSAGE

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