TY - JOUR
T1 - Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis c infection
AU - Lawitz, Eric
AU - Rodriguez-Torres, Maribel
AU - Denning, Jill M.
AU - Albanis, Efsevia
AU - Cornpropst, Melanie
AU - Berrey, Michelle M.
AU - Symonds, William T.
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
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U2 - 10.1128/AAC.01263-12
DO - 10.1128/AAC.01263-12
M3 - Article
C2 - 23263000
AN - SCOPUS:84874043353
VL - 57
SP - 1209
EP - 1217
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 3
ER -