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 Res. 2013 Sep;99(3):214-20. doi: 10.1016/j.antiviral.2013.05.015. Epub 2013 Jun 7.


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 >10(6)IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log₁₀IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg 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.

Trial registration: NCT00704184.

Keywords: AE; AUC; BMI; BUN; C(max); C(trough); CI; CRU; DAA; Dose-ranging; EC(50); ECG; Efficacy; GMR; GT; HCV; IC(50); IRF-3; LLoQ; MRL; Merck Research Laboratories; Monotherapy; NS3/4A; PCR; PD; PEG-IFN; PI; PK; Pharmacokinetics; RAVs; RBV; SAE; SEAP; SVR; Safety; T(max); ULN; adverse event; area under the concentration-time curve; bid; blood urea nitrogen; body mass index; clinical research unit; confidence interval; direct-acting antiviral; electrocardiogram; genotype; geometric mean ratio; half-maximal effective concentration; half-maximal inhibitory concentration; hepatitis C virus; interferon regulatory factor 3; lower limit of quantitation; maximum concentration; maximum time to reach C(max); nonstructural protein 3/4A; once daily; pegylated interferon; pharmacodynamic(s); pharmacokinetic(s); polymerase chain reaction; protease inhibitor; qd; resistance-associated amino acid variants; ribavirin; secreted alkaline phosphatase; serious adverse event; sustained viral response; t(1/2); terminal half-life; trough concentration; twice daily; upper limit of normal.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacokinetics*
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Drug Resistance, Viral
  • Female
  • Genotype
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology
  • Hepacivirus / genetics
  • Hepacivirus / isolation & purification
  • Hepatitis C / drug therapy*
  • Hepatitis C / virology
  • Humans
  • Indoles / adverse effects
  • Indoles / pharmacokinetics*
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Protease Inhibitors / adverse effects
  • Protease Inhibitors / pharmacokinetics
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Young Adult


  • Antiviral Agents
  • Carrier Proteins
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • NS3 protein, hepatitis C virus
  • NS4A cofactor peptide, Hepatitis C virus
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • vaniprevir

Associated data