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 clinicallyrelevant changes in vital signs or ECG parameters. Baseline demographic characteristics were comparable across treatment groups in both studies. DCV was readily absorbed, with median tmax of ~ 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 tmax of ~ 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 - 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.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of apixaban in healthy Japanese male subjects.

OBJECTIVE: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of apixaban in healthy Japanese male subjects. METHODS: The study was conducted using three sequential dose panels: apixaban 2.5 mg, 5 mg, and 10 mg given twice daily. For each dose panel, subjects were randomly assigned to receive oral apixaban (n = 6) or matching placebo (n = 2) for 7 days. The pharmacokinetics of apixaban and effect on pharmacodynamic variables (clotting assays and anti-Xa activity) were assessed on day 1 and day 7 of treatment. Safety was assessed throughout the study. Only after the preceding dose was confirmed to be safe and well-tolerated subjects were enrolled into the next-higher-dose panel. RESULTS: Apixaban was safe and well-tolerated in these healthy Japanese male subjects across the doses evaluated. On day 7, peak plasma concentrations were reached ~ 3 hours postdose, and increases in peak plasma concentration (C(max)), trough plasma concentration, and area under the plasma concentration-time curve across one dosing interval (12 hours) were tested dose-proportional across the dose range. A modest degree of accumulation was observed that was similar for all doses (accumulation index of 1.7 to 2.0), and renal clearance was consistent across doses (0.91 L/h - 1.07 L/h). Exposure-dependent prolongation of prothrombin time, activated partial thromboplastin time, modified prothrombin time, and increases in anti-Xa activity were observed after single and multiple doses of apixaban. CONCLUSIONS: Apixaban was safe and well-tolerated in healthy Japanese subjects. The pharmacokinetic profile of apixaban following multiple twice-daily doses was linear, and exposure parameters such as C(max), observed at ~ 3 hours post-dose, and area under the plasma concentration-time curve increased in a dose-proportional manner. Pharmacodynamic profiles closely followed the apixaban plasma concentration-time profiles.