Clinical Pharmacology Corner: FDA Approves MAVYRET (Glecaprevir and Pibrentasvir)

FDA Approves MAVYRET (Glecaprevir and Pibrentasvir) for Patients With Chronic HCV Infection Without Cirrhosis and With Compensated Cirrhosis (Child-Pugh A), Including Patients Who Have Genotype 1 Infection and Certain Previous HCV Treatments

On August 3, 2017, the U.S. Food and Drug Administration (FDA) approved MAVYRET (glecaprevir and pibrentasvir) for treatment of patients with:

• Chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A). 
• Adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both.

The approved recommended dosage of MAVYRET is three tablets (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) taken once daily with food. Treatment durations range from 8 to 16 weeks based on HCV genotype, treatment history, and cirrhosis status as described in the full prescribing information (link below).  

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with MAVYRET. HBV reactivation has been reported in HCV/HBV co-infected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Use of MAVYRET is contraindicated with atazanavir, rifampin, or in patients with severe hepatic impairment (Child-Pugh C).

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: MAVYRET is a fixed-dose combination of glecaprevir and pibrentasvir, which are direct-acting antiviral agents against the hepatitis C virus. Glecaprevir inhibits HCV NS3/4A protease and pibrentasvir inhibits HCV NS5A.
• Observed Exposure in Target Population: Relative to healthy subjects, glecaprevir C_max was 51% lower and AUC_24,ss was similar, and pibrentasvir C_max was 63% and AUC_24,ss was 34% lower in HCV-infected subjects without cirrhosis.
• Absorption: T_max was 5 hours for both glecaprevir and pibrentasvir.  
• Food Effect: Mean systemic exposure with moderate to high fat meals increased 83-163% for glecaprevir and 40-53% for pibrentasvir, relative to fasting.
• Plasma Protein Binding: Glecaprevir, 97.5%; and pibrentasvir, > 99.9%. 
• Terminal Half-Life: Glecaprevir, 6 hours; and pibrentasvir, 13 hours. 
• Metabolism: Glecaprevir exhibited limited metabolism in vitro, predominantly by CYP3A. Pibrentasvir is not metabolized. 
• Excretion: Both glecaprevir and pibrentasvir undergo biliary-fecal excretion.  Following administration of a single radiolabeled dose, 92.1% of the glecaprevir dose was recovered in feces and 0.7% in urine, whereas 96.6% of the pibrentasvir dose was excreted in feces.  

Drug Interactions

Contraindicated with MAVYRET:

• Atazanavir 
• Rifampin

Coadministration with MAVYRET not recommended:

• Carbamazepine
• Certain antiretrovirals (darunavir, lopinavir, ritonavir, and efavirenz)  
• Certain HMG-CoA reductase inhibitors (atorvastatin, lovastatin, and simvastatin)
• Ethinyl estradiol-containing products (e.g., combined oral contraceptives) 
• In patients requiring stable cyclosporine doses > 100 mg per day 
• St. John’s wort

Recommendations for other drugs if coadministered with MAVYRET: 

• Dabigatran etexilate: Refer to the dabigatran etexilate prescribing information for dose modifications in combination with P-gp inhibitors in the setting of renal impairment.
• Digoxin: Measure serum digoxin concentrations before initiating MAVYRET. Reduce digoxin concentrations by decreasing the dose by approximately 50% or by modifying the dosing frequency and continue monitoring.
• Other HMG-CoA reductase inhibitors:  Reduce pravastatin dose by 50%. Rosuvastatin dose should not exceed 10 mg. Use the lowest approved dose of fluvastatin or pitavastatin; if higher doses are needed, use the lowest necessary fluvastatin or pitavastatin dose based on a risk/benefit assessment.

Use in Specific Populations

Hepatic Impairment:

• Severe (Child-Pugh C): contraindicated with MAVYRET
• Moderate (Child-Pugh B): not recommended with MAVYRET
• Mild (Child-Pugh A): no dosage adjustment of MAVYRET required

Age [18-88 years], sex, race/ethnicity, body weight or renal impairment (i.e., mild, moderate, severe, or end-stage renal impairment (GFR estimated using Modification of Diet in Renal Disease) with or without dialysis) did not have a clinically significant impact on the pharmacokinetics of glecaprevir or pibrentasvir.

Efficacy and Safety

The efficacy of MAVYRET was demonstrated in eight clinical trials in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection and compensated liver disease (including Child-Pugh A cirrhosis) according to treatment history and cirrhosis status. The primary endpoint across all clinical trials was sustained virologic response (SVR12), defined as HCV RNA less than the lower limit of quantification (LLOQ) of 15 IU/mL at 12 weeks after the end of treatment. Additional information regarding the efficacy trials can be found in the full prescribing information (link below).

The most commonly reported adverse reactions (> 10%) are headache and fatigue.

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Full prescribing information is available at https://go.usa.gov/xRmJ2.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

We always welcome your thoughts regarding the format, content, and utility of the communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov