Y. Choi,1 S. Yoon,1 E. Ismatova,1 Y. Kumagai,2 H. Lee,1 K. Yu,1 J. Chung,3 I. Jang1; 1Seoul National University College of Medicine and Hospital, Seoul, Korea, Republic of, 2Clinical Trial Center, Kitasato University Hospital, Kitamoto, Japan, 3Seoul National University Bundang Hospital, Seongnam, Korea, Republic of
BACKGROUND: Telaprevir is a hepatitis C virus protease inhibitor, approved in the United States, Europe, and Japan. This study evaluated the pharmacokinetic (PK) profile, safety, and tolerability of telaprevir in healthy Korean population.
METHODS: Single ascending dose (SAD) study was conducted in three groups (500, 750 and 1250 mg, six subjects each) in the fasted state. In the multiple dose study, eight subjects received 750 mg of telaprevir once on Day 1 and every 8 hours from Day 2 until the morning of Day 6 in the fed state. Serial blood samples for PK analysis were collected up to 24 hours and 7 days in SAD and multiple dose study, respectively. PK parameters were calculated using non-compartmental analysis. Safety and tolerability profiles were evaluated throughout the study.
RESULTS: Median time to peak concentration (Tmax) and mean half-life (t1/2) in the SAD study were 3.75, 5.00, 4.50 and 5.64, 5.37, 9.32 hours in 500, 750 and 1250 mg dose groups, respectively. Peak concentrations (Cmax) were 0.247 ± 0.111, 0.514 ± 0.238 and 0.448 ± 0.228 μg/mL, and the area under the concentration-time curve (AUC0-t) were 1.76 ± 0.76, 4.23 ± 2.19 and 4.12 ± 2.50 μg•h/mL (mean ± SD) in each groups. Dose proportionality for Cmax and AUC0-t in this range was not confirmed due to large variability. In multiple dose study, steady state was reached after Day 3. Geometric mean ratio of Cmax, AUC0-t in fed state vs. fasting state and its 90% confidence interval were 4.918 (3.280 to 7.373), and 4.81 (2.95 to 7.86), respectively. All of the adverse events (AEs) were mild and there was no discontinuation due to AEs.
CONCLUSION: In single dose range of 500 to 1250 mg of telaprevir, dose linearity was not clear. Absorption has increased in fed state at 750 mg dose, and telaprevir was well tolerated in single dose of up to 1250 mg and multiple doses of 750 mg.