부산대학교 도서관

Background & Aims: GS-5885 is an inhibitor of the hepatitis C virus (HCV) NS5A protein and exhibits potent suppression of genotype 1 HCV replicons. The safety, tolerability, pharmacokinetics, antiviral activity, and resistance profile of once-daily GS-5885 doses of 1–90mg were evaluated in patients with chronic genotype 1 HCV. Methods: Genotype 1 HCV-infected patients were randomized to 3days of once-daily (QD) dosing with placebo (n=12) or GS-5885 1mg (n=10), 3mg (n=10), 10mg (n=20), 30mg (n=10), or 90mg (n=10). Plasma samples for pharmacokinetics, HCV RNA, and NS5A sequencing were collected through day 14. Results: GS-5885 was well tolerated and resulted in median maximal reductions in HCV RNA ranging from 2.3 log10 IU/ml (1mg QD) to 3.3 log10 IU/ml (10mg QD in genotype 1b and 30mg QD). Emax modeling indicated GS-5885 30mg was associated with>95% of maximal antiviral response to HCV genotype 1a. HCV RNA reductions were generally more sustained among patients with genotype 1b vs. 1a. Three of 60 patients had a reduced response and harbored NS5A-resistant virus at baseline. NS5A sequencing identified residues 30 and 31 in genotype 1a, and 93 in genotype 1b as the predominant sites of mutation following GS-5885 dosing. Plasma pharmacokinetics was consistent with QD dosing. Conclusions: During 3days of monotherapy, low doses of GS-5885 demonstrated significant antiviral activity in genotype 1a and 1b HCV-infected patients. GS-5885 is currently being evaluated in combination with direct antiviral regimens with and without peginterferon. [Copyright &y& Elsevier]