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 journalArticle

25 Citations (Scopus)

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
Pages (from-to)214-220
Number of pages7
JournalAntiviral Research
Volume99
Issue number3
DOIs
StatePublished - Sep 2013

Fingerprint

Protease Inhibitors
Hepacivirus
Antiviral Agents
Pharmacokinetics
Genotype
Safety
Infection
Placebos
Virus Diseases
RNA
MK-7009
hepatitis C virus NS3 protein
Chronic Hepatitis C
Drug-Related Side Effects and Adverse Reactions
Nausea
Diarrhea
Electrocardiography
Therapeutics
Viruses
Amino Acids

Keywords

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

ASJC Scopus subject areas

  • Virology
  • Pharmacology
  • Medicine(all)

Cite this

Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection : Safety, antiviral activity, resistance, and pharmacokinetics. / Lawitz, Eric; Sulkowski, Mark; Jacobson, Ira; Kraft, Walter K.; Maliakkal, Benedict; Al-Ibrahim, Mohamed; Gordon, Stuart C.; Kwo, Paul; Rockstroh, Juergen Kurt; Panorchan, Paul; Miller, Michelle; Caro, Luzelena; Barnard, Richard; Hwang, Peggy May; Gress, Jacqueline; Quirk, Erin; Mobashery, Niloufar.

In: Antiviral Research, Vol. 99, No. 3, 09.2013, p. 214-220.

Research output: Contribution to journalArticle

Lawitz, E, Sulkowski, M, Jacobson, I, Kraft, WK, Maliakkal, B, Al-Ibrahim, M, Gordon, SC, Kwo, P, Rockstroh, JK, Panorchan, P, Miller, M, Caro, L, Barnard, R, Hwang, PM, Gress, J, Quirk, E & Mobashery, N 2013, 'Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics', Antiviral Research, vol. 99, no. 3, pp. 214-220. https://doi.org/10.1016/j.antiviral.2013.05.015
Lawitz, Eric ; Sulkowski, Mark ; Jacobson, Ira ; Kraft, Walter K. ; Maliakkal, Benedict ; Al-Ibrahim, Mohamed ; Gordon, Stuart C. ; Kwo, Paul ; Rockstroh, Juergen Kurt ; Panorchan, Paul ; Miller, Michelle ; Caro, Luzelena ; Barnard, Richard ; Hwang, Peggy May ; Gress, Jacqueline ; Quirk, Erin ; Mobashery, Niloufar. / Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection : Safety, antiviral activity, resistance, and pharmacokinetics. In: Antiviral Research. 2013 ; Vol. 99, No. 3. pp. 214-220.
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