Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of GSK2336805, an Inhibitor of Hepatitis C Virus (HCV) NS5A, in Healthy Subjects and Subjects Chronically Infected with HCV Genotype 1

Antimicrob Agents Chemother. 2013 Oct;57(10):5037-44. doi: 10.1128/AAC.00910-13. Epub 2013 Jul 29.

Wilfret DA, Walker J, Adkison KK, Jones LA, Lou Y, Gan J, Castellino S, Moseley CL, Horton J, de Serres M, Culp A, Goljer I, Spreen W.

GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Abstract

GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metabolism, and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, reductions in HCV RNA were observed within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log reduction in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median tmax (time to maximum concentration of drug in serum) of 4.5 versus 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals. (This study has been registered at ClinicalTrials.gov under registration no. NCT01277692.).

PMID: 23896477 [PubMed - in process]

Source

Also See: A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety, Antiviral Activity, and Pharmacokinetics of GSK2336805 When Given as Monotherapy and in Combination With Peginterferon alfa-2a and Ribavirin in Hepatitis C Virus Genotype 1-infected Treatment-naive Subjects