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The FDA approved 42 drugs and biologics of note in 2012. Sixteen are first-in-class agents indicated for the management of a variety of conditions (see Table 70-1). The rest are agents pharmacologically similar to others already marketed (see part 2 of this series). Several of the 2012 pharmacological "firsts" represent therapies that target a specific genetic anomaly (see Table 70-1). Two approvals, anthrax antitoxin (see Table 70-1) and the new levofloxacin indication for plague (see part 2 of this series) were approved under FDA's Animal Efficacy Rule, which is used in cases where it is not feasible or ethical to conduct randomized controlled trials in humans. One new agent, cobicistat, is the first drug approved specifically as a pharmacokinetic enhancer. Cobicistat is an alternative to ritonavir for "boosted" antiretroviral therapy for HIV injections. Two are new radiologic diagnostic agents: Choline C-11 to help detect prostate cancer recurrence and florbetapir F 18 [amyvid] to help measure the density of brain β-amyloid plaques in patients with cognitive decline. Allogeneic cultured keratinocytes and fibroblasts in bovine collagen (GINTUIT) was approved and represents the first cell-based dental product for wound healing following mucogingival manipulation. GINTUIT is a cell "scaffold" product for topical administration that secrets human growth factors, cytokines, and extracellular matrix proteins to catalyze tissue regeneration and repair.1 The zilver ptx, a drug-eluting stent for placement in the femoropopliteal artery represents another first to treat peripheral artery disease. The stent is coated with paclitaxel, a drug proven to reduce the rate of restenosis.2 Finally, four noteworthy diagnostic tests that facilitate optimization of targeted drug therapies were licensed in 2012:
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THERASCREEN FRAS RGQ PCR KIT: a genetic test for the detection of the KRAS gene mutation for the purpose of avoiding unwarranted use of cetuximab (ERIBITUX) in patients with colon cancer who are resistant to the pharmacological action of this medication.3
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COBAS AMPLIPREP/COBAS TAQMAN CMV TEST: a viral load test to gauge antiviral treatment effectiveness in patients who develop CMV infections following solid organ transplants.4
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VERIGENE GP BLOOD CULTURE NUCLEIC ACID TEST: a rapid test that can identify 12 different bacterial causes of sepsis along with three genes that confer resistance to antibiotics commonly selected for initial (empirical) therapy.5
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STRATUFY JVC ANTIBODY ELISA TEST: a test to gauge the risk of progressive multifocal lelukoencephalopathy in patients being treated or being considered for treatment with natalizumab (TYSABRI).6
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First-In-Class New Drug Monographs
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Cobicistat (GS-9350) is both a substrate and inhibitor of cytochrome P450 3A4 and 2D6. It is marketed in a fixed-dose combination tablet with elvitegravir (an integrase inhibitor), emtricitabine (a nucleoside reverse transcriptase inhibitor), and tenofovir disoproxil fumarate (a nucleotide analog reverse transcriptase inhibitor) under the brand name stribild. Similar to low-dose ritonavir, cobicistat is included in the combination as a pharmacokinetic enhancer to "boost" plasma levels of the integrase inhibitor, elvitegravir, for the treatment of HIV infection.7, 8, 9, 10 In a head-to-head comparison, cobicistat compared favorably to ritonavir.8 Unlike ritonavir, cobicistat lacks antiretroviral activity. In addition to its cytochrome P450 effects, cobicistat also inhibits P-glycoprotein and the BCRP, OATP1B1, and OATP1B3 membrane transporter proteins (see Chapter 5. Membrane Transporters and Drug Response). Cobicistat is highly protein bound and has an elimination half-life of approximately 3.5 hours. As is predictable from the pharmacology, cobicistat is associated with many significant drug-drug interactions. Therefore, caution is warranted when starting or stopping concomitant therapies. The structure of cobicistat is shown in Figure 70-1.
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Crofelemer (fulyzaq) is a plant flavonoid derived from an extract of Croton lechleri Müll. Arg., which is native to South America.11, 12 Crofelemer acts to reduce watery stool output by inhibiting two chloride ion channels that regulate secretion of chloride and fluid from intestinal epithelial cells: (1) cyclic adenosine monophosphate(cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel, and (2) the calcium-activated chloride ion channels (CaCC) on the luminal membrane of enterocytes. Crofelemer is an oligomeric proanthocyanidin mixture composed mainly of (+)-catechin, (-)-epicatechin, (+)-gallocatechin, and (-)-epigallocatechin monomer units linked in random sequence (see Figure 70-2). Crofelemer is approved for the control of chronic diarrhea in patients with HIV/AIDS. Crofelemer has not been studied in patients with concomitant gastrointestinal diseases (e.g., ulcerative colitis, Crohn's disease, celiac sprue, etc.), but is under investigation for use against acute types of dehydrating diarrhea, particularly diarrhea caused by bacterial endotoxins that increase gut levels of cAMP, such as infection with Vibrio cholerae and Escherichia coli.11 To date, studies of crofelemer for irritable bowel syndrome have been disappointing.11 At the approved dose of 125 mg twice daily, crofelemer in conjunction with antiretroviral therapy, appears to be well tolerated with a low incidence of unwanted effects. Crofelemer has a low oral bioavailability (below the limits of detection) and thus acts locally in the gut. The drug is not known to inhibit peristalsis11 but local inhibition of cytochrome P450 3A isozymes and MRP2 and OATP1A2 transporters has been demonstrated. Crofelemer is also thought to block pores used by viruses to gain entry into cells and is under investigation as a topical protectant against skin and respiratory viruses.11
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Glucarpidase [carboxypeptidase G2] (voraxaze) is a recombinant form of a bacterial enzyme that cleaves methotrexate to the inactive metabolite, 2,4-diamino-N10-methylpteroic acid (DAMPA), and to the amino acid, glutamate12 see hyperlinked figure captioned "The reaction catalyzed by glucarpidase (CPG2)"). Headed by Bruce A. Chabner M.D., a group working at the National Cancer Institute in the Laboratory of Chemical Pharmacology in 1972, was the first to demonstrate that enzymatic cleavage of methotrexate in plasma was a viable strategy to reduce the toxicity from high-dose antifolate therapies.13 Available for compassionate use since the 1990s,14 glucarpidase is used for rapid reduction of toxic plasma methotrexate concentrations when clearance is delayed by impaired renal function or when renal toxicity is anticipated following accidental overdose. Rapid catabolism of methotrexate in the bloodstream by glucarpidase reduces systemic exposure of the kidneys to the toxin by providing an alternative (non-renal) pathway for elimination of methotrexate from the plasma. Glucarpidase has no effect on intracellular methotrexate actions because distribution of the enzyme is restricted to plasma. Therefore, glucarpidase does not replace leukovorin rescue for patents receiving high-dose methotrexate regimens. Leukovorin is a substrate for glucarpidase, however, so the two should not be administered within 2 hours before or after each other. Glucarpidase is well tolerated following IV bolus administration over 5 minutes; unwanted effects include transient paraesthesia, flushing, nausea, vomiting, pruritus, headache, and allergic reactions. Clinicians should be aware that the glucarpidase breakdown product of methotrexate, DAMPA, interferes with methotrexate immunoassays (but not chromatographic assays) for 48 hours following glucarpidase administration. Glucarpidase is administered as a single intravenous injection of 50 units/kg. The potency of one unit of glucapidase corresponds to the enzymatic cleavage of 1 μmol/L of methotrexate per minute at 37 °C. Serum glucarpidase activity declines with a mean elimination half-life of 5.6 hours. In clinical practice, the dose is repeated as clinically indicated. The treatment is expensive: on average the manufacturer expects four 1,000-unit vials to be used for each episode of methotrexate toxicity at a cost of approximately $90,000/treatment.15
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Ingenol mebutate [ingenol-3-angelate] (picato) is a purified extract from the sap of the plant Euphorbia peplus that is indicated for the topical treatment of actinic keratosis.16 The irritant sap contained in all members of the euphorbia plant family is widely used around the world as a traditional remedy for a variety of medicinal purposes.17 The mechanism of action of ingenol mebutate against actinic keratosis is complex and involves death of dysplastic keratinocytes by primary necrosis (through toxic effects on the plasma membrane and mitochondria) and activation of a protein kinase C-mediated local inflammatory response characterized by neutrophil infiltration and subsequent antibody-dependent cellular cytotoxicity of residual tumor cells.18, 19, 20 In addition, ingenol mebutate is thought to be transported to subepidermal tissues by P-glycoprotein where it disrupts the vasculature of the lesion.21 Unlike other topical treatments for actinic keratosis (fluorouracil, imiquimod, etc), ingenol mebutate rapidly reduces lesions after application for only 2-3 consecutive days.16 Like other topical treatments, recurrence of cleared lesions is problematic. Ingenol mebutate is marketed in 2 strengths, 0.015% gel for scalp and face lesions and 0.05% gel for lesions on extremities and trunk. Transient local skin irritation including erythema, scaling, crusting, edema, vesiculation, pustulation, ulceration, pain, and itching are common side effects. The structure of ingenol mebutate is shown in Figure 70-3.
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Lomitapide mesylate (juxtapid) lowers plasma LDL-C, total cholersterol, apolipoprotein B, and non-high density lipoprotein cholesterol levels by inhibiting microsomal triglyceride transfer protein (MTP) to prevent the assembly of apolipoprotein B-containing lipoproteins and thereby inhibits the synthesis of VLDL. It is indicated for patients with homozygous familial hypercholesterolemia in conjunction with a low-fat diet and other aggressive lipid management measures, including LDL apheresis where available.22 Homozygous familial hypercholesterolemia is a rare genetic disease resulting from mutations in both copies of the low-density lipoprotein receptor gene.23 Patients with various forms of this condition experience accelerated atherosclerosis and are resistant to typical lipid-lowering drug regimens. Lomitapide, as demonstrated by a single-arm, open-label 78-week study of 29 patients, is both highly effective and potentially highly toxic. Availability of the drug in the U.S. is restricted by the terms of the FDA-mandated juxtapida Risk Evaluation and Mitigation Strategy (REMS) program. Significant toxicities of the drug include hepatotoxicity, embryo-fetal toxicity, and gastrointestinal intolerability. Gastrointestinal intolerability of lomitapide may adversely affect the absorption of other medications. Lomitapide is contraindicated during pregnancy; a negative pregnancy test and a reliable form of contraception are necessary before starting therapy. Exposure to high-doses of the drug significantly increased the incidences of tumors in some pre-clinical test models. Concomitant therapy with strong and moderate CYP3A4 inhibitors, including grapefruit juice, is contraindicated due to increased systemic exposure and the potential for excess toxicity. Lomitapide interacts with warfarin, requiring careful monitoring of patients receiving concomitant therapy. Patients receiving lomitapide require supplemental vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Lomitapide has an absolute bioavailability of approximately 7% and must be taken 2 hours after the last meal of the day to accommodate the 5-6 hour time needed to achieve peak serum levels. Lomitapide is metabolized extensively in the liver to inactive metabolites. The drug is a substrate and inhibitor of CYP3A4. The major metabolic pathways of detoxification include oxidation, oxidative N-dealkylation, glucuronide conjugation, and piperidine ring opening. The major route of elimination is excretion through kidneys, but approximately 30% is excreted unchanged in feces. The terminal half-life is approximately 40 hours. Lomitapide is an inhibitor, but not a substrate, of P-glycoprotein. The recommended starting dosage of lomitapide is 5 mg daily, escalated gradually and as tolerated up to 60 mg daily with monitoring and adjustments according to the recommendations published in the drug labeling. The chemical structure of lomitapide mesylate is shown in Figure 70-4.
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Ivacaftor (kalydeco) was selected for development from a library of ~228,000 compounds screened for activity as cystic fibrosis transmembrane conductance regulator (CFTR) potentiators.24 The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor increases chloride transport by potentiating the channel-open gating of the G551D-CFTR protein.25 Ivacaftor is intended for the treatment of cystic fibrosis in patients who have tested positive for the G551D mutation in the CFTR gene.25 The G551D mutation is present in 4–5% of patients with cystic fibrosis and ivacaftor is known not to be efficacious in the larger population of patients, particularly those who are homozygous for the F508del gene mutation. Liver function monitoring is necessary before the start of therapy and periodically during treatment with ivacaftor. The usual dose is 150 mg taken twice daily with a fatty food. Fatty foods are known to increase the systemic exposure to ivacaftor by 2- to 4-fold. The dose of ivacaftor must be reduced in patients with pre-existing liver impairment and in patients who develop significant elevations in liver enzymes during therapy. Ivacaftor should be avoided in patients with serious hepatic dysfunction. Ivacaftor and its active metabolite, M1, are CYP3A4 substrates and inhibitors, as well as inhibitors of P-glycoprotein. Therefore, multiple significant interactions with other commonly administered medications are predictable and require careful dose regulation to avert toxicities. Patients should be counseled to avoid grapefruit and Seville oranges while taking ivacaftor. In cystic fibrosis patients with the G5513 mutation, ivacaftor produces a modest (10-12%) improvement in FEV1 and is associated with a statistically significant reduction in pulmonary exacerbations. At $294,000 per patient per year, the drug is costly.24 The chemical structure of ivacaftor is shown in Figure 70-5.
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Lorcaserin (belviq) is a serotonin 5-HT2C receptor agonist intended to be used for a 12-week trial in conjunction with a reduced-calorie diet and physical activity for weight loss. Approximately 50% of patients will achieve >5% weight loss during the first 12 weeks of therapy, and for this subset, the drug may be continued for chronic weight maintenance.26 5-HT2C receptors are found in the central nervous system.27 Lorcaserin, which distributes to the cerebrospinal fluid and central nervous system, is thought to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus.27 POMC is a precursor for α-melanocortin stimulating hormone, which has been proven to act on melanocortin-4 receptors to decrease food intake.28 There are indications that lorcaserin may have abuse potential. Other undesired effects include serotonin syndrome (particulary when used in combination with other serotonergic drugs), confusion, somnolence, fatigue, memory problems, attention disturbances, euphoria, dissociation, dizziness, headache, hypoglycemia, priapism, bradycardia, elevated prolactin levels, and valvulopathy. Lorcaserin is contraindicated in pregnancy (FDA category X) and is associated with the development of mammary fibroadenomas in female rats. The drug should not be administered in combination with other serotonergic or dopaminergic drugs, including 5-HT2B receptor agonists (e.g., cabergoline). Lorcaserin has a plasma half-life of ~11 hours and is ~70% bound to plasma proteins. Lorcaserin is extensively metabolized to inactive metabolites in the liver by multiple enzymatic pathways and the drug inhibits CYP2D6. Lorcaserin is not recommended for patients with creatinine clearance <30mL/minute or patients with end stage renal disease. The usual dose of lorcaserin is 10 mg taken twice daily. The chemical structure of lorcaserin is shown in Figure 70-6.
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Mirabegron (myrbetriq) is a beta-3 adrenergic receptor agonist intended for the management of urinary urgency, frequency, and urge incontinence.29 Via activation of G proteins and adenyl cyclase, beta-3 adrenergic agonists cause direct relaxation of detrusor smooth muscle during filling, thereby prolonging the storage phase of the urinary bladder fill-void cycle. 30 While the measurable clinical outcome that is achieved with mirabegron is between 1 and 2 fewer voids per day than without the drug, patients subjectively report a favorable impression for the therapy, particularly as it relates to the potential for fewer nighttime awakenings due to nocturia.31 Beta-3 adrenergic agonists may improve patients' subjective perception of urgency through inhibition of bladder afferents.30 The starting dose of mirabegron is 25 mg daily. For patients with severe renal failure or moderate liver disease, 25 mg is the maximum daily dose. Others can have the dose increased to 50 mg daily if tolerated. Eight weeks of therapy is necessary to attain the maximal level of benefit. The tolerability of mirabegron compared to placebo is favorable with headache and dose-dependent increase in blood pressure and pulse being the most commonly reported side effects. Mirabegron is not recommended for patients with end-stage renal disease, uncontrolled hypertension, or independent risk factors for urinary retention. Combination therapy with antimuscarinic drugs has not been studied due to the risk of precipitating iatrogenic urinary retention. Excretion into breast milk is predicted, so miraberon is not recommended for use by nursing mothers. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, P-glycoprotein, and OCT1, OCT2, and OCT3. Mirabegron is an inhibitor of CYP2D6 and CYP3A. Caution is advised if mirabegron is co-administered with CYP2D6 substrates, especially narrow therapeutic index drugs, such as thioridazine, flecainide, and propafenone. Mirabegron potentiates the effects of digoxin necessitating consideration of a downward adjustment of the digoxin dose and careful monitoring of serum digoxin levels. The chemical structure of mirabegron is shown in Figure 70-7.
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Ocriplasmin (jetrea) is a recombinant truncated form of the human proteolytic enzyme, plasmin.32 It is marketed as a single-dose intravitreal injection as an alternative to surgery for the dissolution of vitreomacular adhesions. Ocriplasmin cleaves the vitreoretinal junction and liquefies the vitreous.33 Clinical experience suggests that ~25% of patients will have their adhesions non-surgically cleared by use of the drug alone. Ocriplasmin is rapidly inactivated by endogenous protease inhibitors including α2-antiplasmin and α2-macroglobulin. Unwanted reactions following ocriplasmin intravitreal injections include vitreous floaters, conjunctival hemorrhage, eye pain, photopsia, blurred vision, macular hole, reduced visual acuity, visual impairment, retinal edema, macular edema, photophobia, vitreous detachment, ocular discomfort, iritis, cataract, dry eye, metamorphopsia, conjunctival hyperemia, and retinal degeneration. Patients must be monitored for intraocular hypertension requiring emergency therapy immediately after administration. Likewise impaired perfusion of the optic nerve and retinal breaks, if they occur, may necessitate emergency management. Lens subluxation and yellowish dychromatopsia have been reported. Due to the threat of significant visual impairment following ocriplasmin administration, treatment of the contralateral eye is not recommended within 7 days of the initial injection. Repeat injections may be associated with immune-mediated reactions and partly because of this, repeated administration of ocriplasmin in the same eye is not recommended.
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Omacetaxine mepesuccinate (homoharringtonine; synribo) is a semi-synthetic derivative of cephalotaxine, a natural alkaloid derived from evergreen Cephalotaxus trees that are indigenous to Asia. In a less pure form, practitioners of traditional Chinese medicine have used extracts of cephalotaxine for their antineoplastic properties.34, 35 Omacetaxine mepesuccinate is approved by FDA as a second-line antineoplastic agent for the treatment for chronic myeloid leukemia (CML) in adults who have failed two or more of the following tyrosine kinase inhibitors: bosutinib [BOSULIF], dasatinib [SPRYCEL], imatinib [GLEEVEC], nilotinib [TASIGNA], and ponatinib [ICLUSIG]. Omacetaxine mepesuccinate appears to work through an interaction with ribosomes to inhibit protein elongation during synthesis. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein which plays a role in the development of Philadelphia chromosome-positive CML. Disruption of protein synthesis also results in apoptosis partially by disrupting the antiapoptotic protein, myeloid cell leukemia-1. Predictably, rapidly dividing cells, including stem cells, are disproportionally sensitive to the effects of omacetaxine. Also predictable, myelosuppression is the dose-limiting toxicity of omacetaxine. Other noteworthy toxicities include hypoglycemia, arrhythmias, acute coronary syndrome, angina, tinnitus, dysfunctions of the eye, and gastrointestinal toxicity. The drug is administered in 28-day cycles by subcutaneous injection with dosage modifications driven by the severity of the toxicities that manifest. The available data appears to signal age- and gender-related differences in cytogenetic and toxic responses to omacetaxine, with patients ≥65 years of age more likely to experience serious hematologic toxicity than younger patients, and men with chronic phase CML more likely to experience a higher cytogenetic response rate than women. Omacetaxine mepesuccinate is primarily hydrolyzed via plasma esterases with little hepatic metabolism. The mean half-life of omacetaxine mepesuccinate following subcutaneous administration is ~6 hours. Omacetaxine is a P-glycoprotein substrate. The chemical structure of omacetaxine is shown in Figure 70-8.
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Perampanel (fycompa) is indicated as an adjunctive treatment for partial-onset seizures.36 Perampanel is a non-competitive antagonist of the α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) glutamate receptor. AMPA receptors are ligand-gated ion channels activated by glutamate, the major excitatory neurotransmitter in the CNS.37 AMPA receptor blockade by perampanel inhibits glutamate from opening AMPA receptors and has the effect of dampening glutamate-stimulated calcium ion currents, thereby reducing the propagation and spread of seizure activity in patients with poorly controlled epilepsy.38, 39 In clinical trials, perampanel reduced mean seizure frequency by ~30% from baseline.40 Perampanel is labeled with a boxed warning due to an association with serious and potentially life-threatening psychiatric events. Aggression, hostility, irritability, anger, homicidal ideation, threats, paranoia, euphoric mood, agitation, anger, mental status changes, disorientation, confusion, anxiety, belligerence, affect lability, physical assault, delusions, and worsening of pre-existing psychiatric conditions have all been reported. Other adverse effects include dizziness, gait disturbance, somnolence, fatigue, headache, nausea, weight gain, vertigo, ataxia, balance disorder, and falls. The use of alcohol in conjunction with perampanel is strongly discouraged. Perampanel is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. The half-life is ~105 hours. Perampanel is 95-96% bound to plasma proteins, mainly albumin and α1-acid glycoprotein. Perampanel is extensively metabolized by CYP3A4, CYP3A5, and other CYP enzymes. Clearance is mainly through feces (48%) and urine (22%). Perampanel is a weak inhibitor of CYP2C8, CYP3A4, UGT1A9 and UGT2B7 and a weak inducer of CYP2B6, CYP3A4/5, and UGT1A1. Perampanel is known to reduce the effectiveness of hormonal oral contraceptives containing levonorgestrel. Dosage adjustments are needed for patients receiving concomitant therapy with enzyme-inducing medications and for patients with hepatic impairment. The staring dose is 2-4 mg daily at bedtime with slow titration up to a maximum of 12 mg daily. Perampanel has demonstrated abuse potential and DEA designation as a controlled substance is currently pending in the U.S. The chemical structure of perampanel is shown in Figure 70-9.
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Raxibacumab (no brand name) is a human IgG1λ monoclonal antibody that binds the protective antigen component of B. anthracis toxin to its cellular receptors to prevent cell entry of the two enzymatic toxin factors (anthrax lethal factor and anthrax edema factor) responsible for the pathogenic effects of anthrax toxin.41 It is indicated as an adjunct to aggressive use of antibiotics for the treatment and prevention of inhalational anthrax intoxication. Raxibacumab has no direct antibacterial activity and does not cross the blood-brain barrier to prevent or treat meningitis. The clinical efficacy of raxibacumab is extrapolated from animal research because it is not ethical to conduct rigorous human clinical trials with anthrax. In a study of rabbits challenged with exposure to spores, more animals survived when treated with levofloxacin plus raxibcumab (82%) compared with levofloxacin alone (65%). Raxibacumab is administered as a single dose of 40 mg/kg infused intravenously over 2.25 hours. Hypersensitivity and infusion site reactions are to be expected.
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Vismodegib (erivedge) selectively binds to the G protein-coupled receptor-like protein Smoothened (SMO) to block intracellular signaling through the hedgehog pathway* (See Figure 70-10). The hedgehog pathway plays an essential role in embryonic development but is normally quiescent in adults.42 Reactivation following one or more mutations in the genes that code for SMO and other proteins in the pathway is implicated in the proliferation of malignant cells in basal cell carcinoma and certain other cancers.42 By blocking the activity of SMO in the hedgehog pathway, vismodegib interferes with tumor cell growth and survival. Vismodegib is indicated for the treatment of metastatic basal cell carcinoma and basal cell carcinoma that has recurred following surgery for patients who are not candidates for surgery or radiation therapy. Vismodegib is contraindicated in pregnancy because the hedgehog pathway is necessary for differentiation of hematopoietic, neural, and mammary stem cells during embryogenesis.42 The embryo-fetal toxicity warning extends for 7 months after cessation of therapy with vismodegib and also necessitates prevention of accidental in utero exposure to the drug through semen, as well as a prohibition against donating blood. The recommended dose of vismodegib is 150 mg orally once daily. Tolerability to the drug is limited by muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. Other reported adverse effects include amenorrhea, hyponatremia, hypokalemia, azotemia, cholestasis, pulmonary embolus, dehydration, syncope, cardiac failure, and pneumonia.43, 44 Acquired resistance to vismodegib followed by tumor progression has been described.44, 45 Vismodegib is a substrate of P-glycoprotein, CYP2C9, and CYP3A4/5, and an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib is only available through specialty pharmacies and the cost is approximately $250/capsule.42, 43 The expected 10-month course of therapy, when tolerated, will approach $75,000.42 The chemical structure of vismodegib is shown in Figure 70-11. At least 6 other SMO inhibitors are currently in development for the treatment of other cancers.44, 45
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