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Pharmacokinetics of hepatitis C virus NS5A inhibitor JNJ‐56914845 (GSK2336805) in subjects with hepatic impairment
Author(s) -
Adkison Kimberly K.,
Gan Jianjun,
ElkoSimms Lucinda,
Gardner Stephen,
Dumont Etienne,
Jones Lori S.,
Saunders Joanne,
Marbury Thomas,
Smith William,
Berg Jolene,
Galloway Christopher,
Stump Patrick J.
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.512
Subject(s) - pharmacokinetics , medicine , ns5a , pharmacology , hepatitis c virus , virology , virus , hepacivirus
Abstract JNJ‐56914845 (GSK2336805) is a hepatitis C virus nonstructural protein 5A inhibitor under development for the treatment of chronic hepatitis C (CHC) infection. This open‐label, parallel‐group, 2‐part study evaluated the pharmacokinetics and safety of a single oral 60 mg dose of JNJ‐56914845 in 4 cohorts: healthy, mild, moderate, and severe hepatic impairment (n = 8/cohort). Severity of hepatic impairment was categorized using Child‐Pugh score, and the healthy subjects were matched for age, sex, body mass index, and smoking status to the moderate hepatic impairment cohort. JNJ‐56914845 plasma AUC 0–∞ was 26%, 52%, and 45% lower in subjects with mild, moderate, and severe hepatic impairment, respectively, relative to healthy subjects with no difference in half‐life among the groups. The apparent oral clearance and volume of distribution were higher in subjects with hepatic impairment. The lower plasma concentrations were largely explained by decreased plasma protein binding in hepatically impaired subjects. One subject with severe hepatic impairment had 2 non‐drug‐related serious adverse events: an esophageal bleed requiring hospitalization, encephalopathy. Although hepatically impaired subjects have lower exposures than healthy matched controls, they had similar or slightly higher exposures than those observed in past studies of noncirrhotic, CHC patients, suggesting that no dose adjustments for hepatic impairment will be needed.