title: Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection.
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.
authors.affiliation: Alamo Medical Research, Ltd., San Antonio, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: Jill M
authors.initials: JM
authors.lastname: Denning
authors.forename: Efsevia
authors.initials: E
authors.lastname: Albanis
authors.forename: Melanie
authors.initials: M
authors.lastname: Cornpropst
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Berrey
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009711:Nucleotides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010919:Placebos; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D009711:Nucleotides; D010919:Placebos; D012367:RNA, Viral