Safety, tolerability, and pharmacokinetics of faldaprevir after single rising doses in healthy subjects

Choi_Loi Yong¹Regina Sennewald²Gerhard Nehmiz²Anne-Marie Quinson¹Fenglei Huang^1*

• ¹Boehringer Ingelheim pharmaceuticals, Ridgefield, United States
• ²Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

Faldaprevir (FDV) is a novel NS3/NS4A inhibitor being developed for the treatment of hepatitis C infection in an interferon-free regimen. This study evaluated the safety, tolerability and pharmacokinetics of FDV following a single dose in healthy male subjects and assessed the effect of food on FDV bioavailability. Part 1: in this placebo-controlled, randomized, single-blind, single-rising-dose part of the study, 64 healthy male subjects were randomized to receive FDV in PEG/TRIS/meglumine solution at one of 8 dose levels (4–1200 mg, n=6 per dose group) or placebo (n=2 per dose group). Part 2: the effect of food on the relative bioavailability (rBA) of FDV 480 mg in solution was evaluated in an open-label, crossover comparison, with and without a high-fat breakfast, in further 10 subjects (8 FDV, 2 placebo). Following single doses of 4–1200 mg FDV, geometric mean (gMean) Cmax and AUC0-inf were 3.57–16500 ng/mL and 254–402000 h*ng/mL respectively, displaying more than dose-proportional increases in exposure. FDV was slowly absorbed with gMean t1/2 and median tmax of 15.5–39.2 hours and 4.0–14.0 hours respectively; both were dose dependent. The urinary excretion of FDV was less than 0.1% of the dose. A high fat breakfast increased systemic exposure to FDV in solution by 14%. FDV was generally well tolerated; subjects who experienced an adverse event (AE) recovered without sequelae and no serious AEs were reported. Indirect bilirubin of >3.0 mg/dL was observed in 2 subjects at 480 mg and 5 subjects at 1200 mg. In conclusion, at single doses of 4 to 1200 mg in healthy male subjects, FDV showed dose-dependent pharmacokinetics and was generally safe and well tolerated. Food had no clinically relevant effect on the rBA of FDV.