Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection

Antimicrob Agents Chemother. 2013 Mar;57(3):1209-17. doi: 10.1128/AAC.01263-12. Epub 2012 Dec 21.

Abstract

We conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naïve patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t(1/2)) values of approximately 1 h for GS-9851 and 3 h for GS-566500. Accumulation (21%) was observed only for GS-331007 (formerly PSI-6206) after multiple dosing. GS-331007 was the primary drug-related moiety in the plasma and urine. Increases in the GS-9851, GS-566500, and GS-331007 maximum concentrations in plasma (C(max)) and area under the concentration-time curve (AUC) were less than dose proportional, particularly at the highest doses. The decline in plasma HCV RNA levels was dose dependent, and a mean maximal change from the baseline of -1.95 log(10) IU/ml was obtained for 400 mg GS-9851, compared with -0.090 log(10) IU/ml for the placebo. Most patients had a decrease in HCV RNA of ≥1.0 log(10) IU/ml after 3 days' dosing with 400 mg GS-9851. No virologic resistance was observed. GS-9851 was generally well tolerated, with no notable differences in adverse event frequency across doses. The pharmacokinetic profile observed in this study was similar to that seen in a single-ascending-dose study in healthy subjects.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Antiviral Agents / blood
  • Antiviral Agents / pharmacokinetics*
  • Antiviral Agents / pharmacology
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Half-Life
  • Hepacivirus / drug effects*
  • Hepacivirus / growth & development
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology
  • Humans
  • Male
  • Middle Aged
  • Nucleotides / blood
  • Nucleotides / pharmacokinetics*
  • Nucleotides / pharmacology
  • Placebos
  • RNA, Viral / antagonists & inhibitors*
  • RNA, Viral / biosynthesis
  • Viral Load / drug effects

Substances

  • Antiviral Agents
  • Nucleotides
  • Placebos
  • RNA, Viral