Pharmacokinetics and Pharmacodynamics of Faldaprevir Following Multiple Oral Rising Doses in Healthy Volunteers and Subjects with Gilbert's Syndrome.

Faldaprevir (FDV) is an investigational NS3/NS4A protease inhibitor for chronic hepatitis C. This study evaluated the safety, tolerability, and pharmacokinetics (PK) of FDV after multiple rising doses in healthy male volunteers and subjects with Gilbert syndrome (GS). In this randomized, double-blind, placebo-controlled study, healthy males received once-daily oral FDV (20, 48, 120 mg [n = 6 per group], 240 mg [n = 5]), or placebo (n = 7). A single dose was given on Day 1, followed by a 72-h washout and 21 days of dosing from day 4. Separately, 9 GS subjects received open-label FDV 240 mg daily for 28 days. PK was assessed after the first and last doses; safety was evaluated throughout. FDV showed greater than dose-proportional increases in exposure (gMean Cmax,ss: 99-5360 ng/mL; AUCτ ,ss: 1740-50,100 h·ng/mL) and time-dependent PK with a linearity index >1. Mean t1/2 was 20-30 h; steady state was reached in 6-7 days with an accumulation ratio of 2.8-3.1. FDV exposure in GS subjects was similar but slightly lower. Total bilirubin increased dose-dependently, with higher indirect bilirubin in GS subjects. FDV exhibited non-linear, time-dependent PK and was generally well tolerated up to 240 mg/day in subjects with or without GS.