Single- and multiple-ascending dose studies to evaluate the safety, tolerability, and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects
Tomomi Shiozaki1, Takayo Ueno1, Hirotaka Nagashima2, Naomi Yamahira1, Masaki Hiraoka1, Tim Eley3, Marc Bifano3, Richard J. Bertz3
1 Bristol-Myers KK, 2 Clinical Research Hospital Tokyo, Tokyo-Clinical Trial Center, Tokyo, Japan, and 3 Bristol-Myers Squibb Research and Development, Hopewell, NJ, USA
DOI 10.5414/CP202186
Abstract
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.
Author Details
Authors
Departments
- 1 Bristol-Myers KK,
- 2 Clinical Research Hospital Tokyo, Tokyo-Clinical Trial Center, Tokyo, Japan, and
- 3 Bristol-Myers Squibb Research and Development, Hopewell, NJ, USA
Address
Tomomi Shiozaki
Bristol-Myers KK
6-5-1, Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan
Email:
[email protected]
Citation
Tomomi Shiozaki, Takayo Ueno, Hirotaka Nagashima, Naomi Yamahira, Masaki Hiraoka, Tim Eley, Marc Bifano, and Richard J. Bertz.Single- and multiple-ascending dose studies to evaluate the safety, tolerability, and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects. 2015; 53: 292-302. doi: 10.5414/CP202186.
