lunes, 14 de marzo de 2016

FDA Clinical Pharmacology Corner: FDA Approves ZEPATIER (Elbasvir and Grazoprevir)

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FDA Approves ZEPATIER® (Elbasvir and Grazoprevir) for the Treatment of Chronic Hepatitis C Infection
On January 28, 2016, the United States Food and Drug Administration (FDA) approved ZEPATIER (elbasvir and grazoprevir) for the treatment of chronic genotype 1 or 4 hepatitis C virus (HCV) infection in adults. The approved recommended dosage of ZEPATIER is one tablet taken orally once daily with or without food for 12 weeks. In genotype 1a patients with certain baseline NS5A polymorphisms or genotype 4 patients who have failed prior treatment with peginterferon alpha (PegIFN) and ribavirin (RBV), ZEPATIER should be administered for 16 weeks in combination with RBV. In genotype 1 patients who have failed treatment with PegIFN, RBV, and an HCV NS3/4A protease inhibitor (boceprevir, simeprevir or telaprevir), ZEPATIER should be administered for 12 weeks in combination with RBV. Each ZEPATIER tablet contains 50 mg of elbasvir and 100 mg of grazoprevir.
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of ZEPATIER
  • MOA: Elbasvir is an inhibitor of HCV NS5A and grazoprevir is an inhibitor of HCV NS3/4 protease. 
  • Absorption (Median Tmax): Elbasvir: 3 hours; grazoprevir: 2 hours 
  • Plasma protein binding: Elbasvir: ~99.9%; grazoprevir: ~98.8%; Both elbasvir and grazoprevir bind to human serum albumin and 1-acid glycoprotein. 
  • Half-life: The mean elimination half-lives of elbasvir and grazoprevir are approximately 24 hours and 31 hours, respectively.
  • Metabolism: Elbasvir and grazoprevir are partially metabolized by CYP3A. 
  • Excretion: The primary route of excretion of elbasvir and grazoprevir is feces. Less than 1% of the administered dose is excreted in urine. 
  • Exposure-Response: Approximately one percent of subjects who received ZEPATIER (with or without ribavirin) experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN), generally at or after 8 weeks of treatment. Exposure-response analyses indicated that occurrence of late ALT elevation was higher in subjects with higher grazoprevir plasma concentrations. No exposure-response relationship for efficacy was identified for elbasvir or grazoprevir at the approved recommended dosage. The presence of baseline NS5A polymorphisms had a significant impact on ZEPATIER efficacy that is unlikely to be overcome with changes to elbasvir dosing (see Safety and Efficacy below).
Drug Interaction Potential
  • The co-administration of OATP1B1/3 inhibitors is contraindicated due to significant increases in grazoprevir exposures. 
  • The co-administration of strong CYP3A inducers and efavirenz is contraindicated due to significant decreases in elbasvir and grazoprevir exposures. The co-administration of moderate CYP3A inducers is not recommended.
  • Co-administration of certain strong CYP3A inhibitors (ketoconazole or cobicistat) is not recommended due to increases in elbasvir and grazoprevir exposures.
  • Frequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse events upon the initiation of co-administration with ZEPATIER is recommended due to an increase in the concentrations of tacrolimus.
  • The maximum recommended daily doses of atorvastatin and rosuvastatin, when co-administered with ZEPATIER, are 20 mg and 10 mg, respectively due to increases in exposures of atorvastatin and rosuvastatin.
  • Statin-associated adverse events such as myopathy should be closely monitored and the lowest necessary dose should be used when co-administering ZEPATIER with fluvastatin, lovastatin, or simvastatin. Co-administration may increase the concentrations of these statins.
Use in Specific Populations
  • Renal Impairment: ZEPATIER can be used in patients with varying degrees of renal impairment without a dose adjustment (including patients on hemodialysis).
  • Hepatic Impairment: ZEPATIER can be used in patients with mild (Child-Pugh A) hepatic impairment. ZEPATIER is contraindicated in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment. 
Safety and Efficacy
The safety and efficacy of ZEPATIER with or without ribavirin were evaluated in clinical trials of 1,373 patients with chronic HCV genotype 1 or 4 infections. Trial populations included patients with compensated cirrhosis, prior PegIFN and RBV treatment failure, HIV co-infection, and chronic kidney disease Stage 4 or 5 including patients on hemodialysis. Depending on the patient population, patients received ZEPATIER once daily with or without ribavirin for 12 or 16 weeks. The primary efficacy endpoint was the percentage of patients who achieved sustained virologic response (SVR) defined as HCV RNA less than the lower limit of quantification 12 weeks after stopping treatment (SVR12). SVR rates ranged from 94% to 97% in genotype 1-infected patients and from 97% to 100% in genotype 4-infected patients across trials for the approved treatment regimens. In genotype 1a-infected patients with certain baseline NS5A polymorphisms, reduced efficacy of ZEPATIER (SVR: 70%) was observed with the 12-week treatment duration. In these subjects, the efficacy was significantly improved when ZEPATIER was administered for 16 weeks in combination with ribavirin. The most common side effects of ZEPATIER were fatigue, headache, and nausea. Approximately one percent of subjects who received ZEPATIER experienced ALT elevations (see Exposure-Response above).

Full prescribing information is available at 
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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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