domingo, 23 de julio de 2017

Clinical Pharmacology Corner: FDA Approves VOSEVI (Sofosbuvir, Velpatasvir, and Voxilaprevir)

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FDA Approves VOSEVI (Sofosbuvir, Velpatasvir, and Voxilaprevir) for Treatment of Adult Patients With Chronic HCV Infection Without Cirrhosis or With Compensated Cirrhosis Who Have Certain Genotype Infections and Previous HCV Treatments
On July 18, 2017, the U.S. Food and Drug Administration (FDA) approved VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) for the treatment of adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have: 
  • Genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor.
  • Genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Additional benefit of VOSEVI over sofosbuvir/velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor.
The approved recommended dosage of VOSEVI is one tablet (sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg) taken orally once daily with food for 12 weeks. Use of VOSEVI is contraindicated with rifampin.
HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAA) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating treatment with VOSEVI. Monitor HCV/HBV coinfected 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.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: VOSEVI is a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir. Sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, velpatasvir, an HCV NS5A inhibitor, and voxilaprevir, an HCV NS3/4A protease inhibitor, each inhibit enzymes required for viral replication. 
  • Observed Exposure in Target Population: Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects, velpatasvir AUC0-24 and Cmax were 41% and 39% lower in HCV-infected subjects, respectively, and voxilaprevir AUC0-24 and Cmax were both 260% higher in HCV-infected subjects.
  • Absorption: Tmax was 2, 4, and 4 hours for sofosbuvir, velpatasvir, and voxilaprevir, respectively.
  • Food Effect: Geometric mean systemic exposure increased 64-144% for sofosbuvir, 40-166% for velpatasvir, and 122-435% for voxilaprevir, relative to fasting. 
  • Plasma Protein Binding: Sofosbuvir, 61-65%; velpatasvir and voxilaprevir, > 99%. 
  • Terminal Half-Life: Sofosbuvir, 0.5 hours; GS-331007, 29 hours; velpatasvir, 17 hours; voxilaprevir, 33 hours. 
  • Metabolism: Sofosbuvir, primarily to GS-331007 via Cathepsin A, CES1, and HINT1; velpatasvir, CYP2B6/CYP2C8/CYP3A4; voxilaprevir, CYP3A4. 
  • Excretion: GS-331007 undergoes glomerular filtration and active tubular secretion; 80% of a single dose of radiolabeled sofosbuvir was excreted in urine, predominantly as GS-331007. Velpatasvir and voxilaprevir undergo biliary excretion, with 94% recovered in feces following a single radiolabeled dose of velpatasvir (77% as parent) and voxilaprevir (40% as parent). In addition, 0.4% of the velpatasvir dose was excreted in the urine.
Drug Interactions
Contraindicated with VOSEVI: Rifampin
Not recommended to be coadministered with VOSEVI:
  • Amiodarone
  • P-gp inducers and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4
  • OATP inhibitors (e.g., cyclosporine)
  • BCRP substrates (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan)
  • Certain anticonvulsants (carbamazepine, phenytoin, phenobarbital, oxcarbazepine)
  • Certain antimycobacterials (rifabutin, rifapentine)
  • Certain antiretrovirals (atazanavir, lopinavir, tipranavir/ritonavir, efavirenz)
  • Certain HMG-CoA reductase inhibitors (rosuvastatin, pitavastatin)
Digoxin: Therapeutic concentration monitoring of digoxin is recommended when coadministered with VOSEVI.
Drugs that increase gastric pH: Separate antacid and VOSEVI administration by 4 hours, H2-receptor antagonists may be administered simultaneously with or staggered from VOSEVI at a dose that does not exceed doses comparable with famotidine 40 mg twice daily. Omeprazole 20 mg can be administered with VOSEVI, and use with other proton pump-inhibitors has not been studied.
Dabagatrin: Clinical monitoring of dabigatran is recommended when coadministered with VOSEVI.
Tenofovir disoproxil fumarate: Monitor for tenofovir-associated adverse reactions in patients receiving VOSEVI concomitantly with a regimen containing tenofovir disoproxil fumarate.
Other HMG-CoA reductase inhibitors: Pravastatin may be administered with VOSEVI at a dose that does not exceed pravastatin 40 mg. For coadministration of atorvastatin, fluvastatin, lovastatin, or simvastatin with VOSEVI, use the lowest approved statin dose. If higher doses are needed, use the lowest necessary statin dose based on a risk/benefit assessment.
Use in Specific Populations
VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). No dosage adjustment of VOSEVI is required for patients with mild hepatic impairment (Child-Pugh A).
The safety and efficacy of VOSEVI have not been established in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite in these patients. No dosage adjustment of VOSEVI is required for patients with mild or moderate renal impairment.
Age (18-85 years), sex, race, and body mass index (BMI) did not clinically significantly impact pharmacokinetics of VOSEVI.
Efficacy and Safety
The efficacy of VOSEVI was demonstrated in two Phase 3 trials in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis (POLARIS-1 and POLARIS-4). Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ (15 IU/mL) at 12 weeks after the cessation of treatment, was the primary endpoint in both trials. Additional information regarding the efficacy trials can be found in the full prescribing information linked below.
The most common adverse reactions (incidence ≥ 10%, all grades) observed with treatment with VOSEVI for 12 weeks were headache, fatigue, diarrhea, and nausea.

Full prescribing information is available at
Visit Drugs@FDA at for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology

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