Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics

Eric Lawitz, Mark Sulkowski, Ira Jacobson, Walter K. Kraft, Benedict Maliakkal, Mohamed Al-Ibrahim, Stuart C. Gordon, Paul Kwo, Juergen Kurt Rockstroh, Paul Panorchan, Michelle Miller, Luzelena Caro, Richard Barnard, Peggy May Hwang, Jacqueline Gress, Erin Quirk, Niloufar Mobashery

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Vaniprevir is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent anti-HCV activity in preclinical models. This placebo-controlled dose-ranging study assessed the safety, tolerability, and antiviral efficacy of vaniprevir monotherapy in patients with genotype 1 chronic HCV infection. Treatment-naive and treatment-experienced non-cirrhotic adult patients with baseline HCV RNA >106IU/ml were randomized to receive placebo or vaniprevir at doses of 125mg qd, 600mg qd, 25mg bid, 75mg bid, 250mg bid, 500mg bid, and 700mg bid for 8days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6log10IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75mg bid. The most commonly reported drug-related adverse events (AEs) were diarrhea (n=5) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing.

Original languageEnglish (US)
Pages (from-to)214-220
Number of pages7
JournalAntiviral Research
Volume99
Issue number3
DOIs
StatePublished - Sep 1 2013
Externally publishedYes

Keywords

  • Dose-ranging
  • Efficacy
  • Monotherapy
  • Pharmacokinetics
  • Safety

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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