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

Eric Lawitz, Maribel Rodriguez-Torres, Jill M. Denning, Efsevia Albanis, Melanie Cornpropst, Michelle M. Berrey, William T. Symonds

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 (t1/2) 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 log10 IU/ml was obtained for 400 mg GS-9851, compared with -0.090 log10 IU/ml for the placebo. Most patients had a decrease in HCV RNA of>1.0 log10 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-ascendingdose study in healthy subjects.

Original languageEnglish (US)
Pages (from-to)1209-1217
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume57
Issue number3
DOIs
StatePublished - Mar 2013

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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