Single- And Multiple-Ascending Dose Studies To Evaluate The Safety, Tolerability, And Pharmacokinetics Of Daclatasvir And Asunaprevir In Healthy Male Japanese Subjects

Objectives: Assess the safety, tolerability, and pharmacokinetic (PK) profiles of daclatasvir (DCV) and asunaprevir (ASV) in healthy male Japanese subjects. Methods: AI444-007 and AI447-005 were phase I, double-blind, placebo-controlled, sequential, single-ascending dose (SAD), and multiple-ascending dose (MAD) studies assessing DCV or ASV, respectively. Eight subjects per panel were randomized to study drug or placebo (3 : 1). In the SAD part of each study, subjects received single oral dose DCV 1/10/50/100/200 mg or ASV 200/400/600/900/1,200 mg. In MAD, subjects received 14-day oral multiple dose DCV 1/10/100 mg once-daily or ASV 200/400/600 mg every 12 hours. Serial PK blood sampling occurred from predose to 72-hours postdose or post-last-dose. Safety and tolerability was assessed throughout. Results: 64 (SAD, n = 40; MAD, n = 24) and 65 (SAD, n = 40; MAD, n = 25) subjects were enrolled in AI444-007 and AI447-005, respectively. DCV and ASV were generally well tolerated, with no serious adverse events or clinically-relevant changes in vital signs or ECG parameters. Baseline demographic characteristics were comparable across treatment groups in both studies. DCV was readily absorbed, with median t(max) of similar to 1 - 2 hours postdose and concentrations declining in a multi-phasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state was achieved between days 4 and 5 of multiple dosing. ASV was readily absorbed, with median t(max) of similar to 2 - 4 hours postdose and concentrations declining in a biphasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state appeared to be achieved between days 3 and 5 of multiple dosing. Conclusions: Results suggest no clinically significant short-term safety signals with DCV and ASV at single or multiple doses in this population.