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

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 >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.

• Authors: 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
• Journal: Antiviral research (Antiviral Res) Vol. 99 Issue 3 Pg. 214-20 (Sep 2013) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 23747481 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Carrier Proteins
• Cyclopropanes
• Indoles
• Intracellular Signaling Peptides and Proteins
• Isoindoles
• Lactams, Macrocyclic
• NS3 protein, hepatitis C virus
• NS4A cofactor peptide, Hepatitis C virus
• Protease Inhibitors
• Sulfonamides
• Viral Nonstructural Proteins
• Proline
• vaniprevir
• Leucine

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antiviral Agents (adverse effects, pharmacokinetics)
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Cyclopropanes
• Drug Resistance, Viral
• Female
• Genotype
• Hepacivirus (drug effects, enzymology, genetics, isolation & purification)
• Hepatitis C (drug therapy, virology)
• Humans
• Indoles (adverse effects, pharmacokinetics)
• Intracellular Signaling Peptides and Proteins
• Isoindoles
• Lactams, Macrocyclic
• Leucine (analogs & derivatives)
• Male
• Middle Aged
• Proline (analogs & derivatives)
• Protease Inhibitors (adverse effects, pharmacokinetics)
• Sulfonamides
• Viral Nonstructural Proteins (antagonists & inhibitors, genetics, metabolism)
• Young Adult