Document Detail

Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for hepatitis C virus, following single ascending doses in healthy subjects.
MedLine Citation:
PMID:  23262999     Owner:  NLM     Status:  MEDLINE    
To investigate the pharmacokinetics, safety, and tolerability of GS-9851 (formerly PSI-7851), a new nucleotide analog inhibitor of hepatitis C virus (HCV), we conducted a double-blind, parallel, placebo-controlled, randomized, single-ascending-dose study. Healthy subjects received oral doses of 25 to 800 mg GS-9851. Peak concentrations of GS-9851 in plasma were achieved more rapidly than those of the metabolites GS-566500 (formerly PSI-352707) and GS-331007 (formerly PSI-6206), with time to maximum concentration of drug in plasma (t(max)) values of 1.0 to 1.8 h, 1.5 to 3.0 h, and 3.0 to 6.0 h, respectively. The majority of systemic drug exposure was from the nucleoside GS-331007, with maximum concentration of drug in plasma (C(max)) and area under the concentration-time curve to the last measurable concentration (AUC(0-t)) values at least 7- and 41-fold higher, respectively, than those obtained for GS-9851 after adjusting for differences in molecular weight. The terminal elimination half-life (t(1/2)) of GS-331007 increased with the dose, achieving a t(1/2) of 25.7 h at 800 mg GS-9851. Dose proportionality was not observed for GS-331007. The majority of drug recovered in urine was in the form of GS-331007, with the percentage of this metabolite in urine samples ranging from 57% to 27% with increasing dose. GS-9851 was generally well tolerated, with no maximum tolerated dose identified. In conclusion, GS-9851 and its metabolites demonstrated a favorable pharmacokinetic profile consistent with once-daily dosing, and therefore, further clinical studies evaluating GS-9851 in HCV-infected patients are warranted.
Jill Denning; Melanie Cornpropst; Stephen D Flach; Michelle M Berrey; William T Symonds
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2012-12-21
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  57     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-15     Completed Date:  2013-07-30     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1201-8     Citation Subset:  IM    
Pharmasset, Inc., Princeton, NJ, USA.
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MeSH Terms
Administration, Oral
Antiviral Agents / blood,  pharmacokinetics*,  pharmacology
Area Under Curve
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Hepacivirus / drug effects*,  growth & development
Hepatitis C, Chronic / drug therapy*,  virology
Middle Aged
Nucleotides / blood,  pharmacokinetics*,  pharmacology
RNA, Viral / antagonists & inhibitors*,  biosynthesis
Viral Load / drug effects
Reg. No./Substance:
0/Antiviral Agents; 0/Nucleotides; 0/Placebos; 0/RNA, Viral

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