title: 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.
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.).
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Wilfret
authors.forename: J
authors.initials: J
authors.lastname: Walker
authors.forename: K K
authors.initials: KK
authors.lastname: Adkison
authors.forename: L A
authors.initials: LA
authors.lastname: Jones
authors.forename: Y
authors.initials: Y
authors.lastname: Lou
authors.forename: J
authors.initials: J
authors.lastname: Gan
authors.forename: S
authors.initials: S
authors.lastname: Castellino
authors.forename: C L
authors.initials: CL
authors.lastname: Moseley
authors.forename: J
authors.initials: J
authors.lastname: Horton
authors.forename: M
authors.initials: M
authors.lastname: de Serres
authors.forename: A
authors.initials: A
authors.lastname: Culp
authors.forename: I
authors.initials: I
authors.lastname: Goljer
authors.forename: W
authors.initials: W
authors.lastname: Spreen
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000998:Antiviral Agents
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