Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of Macitentan, a New Endothelin Receptor Antagonist, in Healthy Japanese Male Subjects

Tolerability, safety, pharmacokinetics, and pharmacodynamics of orally administered macitentan at 3 and 10 mg once daily for 10 days were investigated in 16 healthy Japanese male subjects in a randomized, placebo-controlled, double-blind, single-center study. Plasma concentrations of macitentan were found to peak at 5 hr, with a mean terminal elimination half-life of approximately 11 hr, for both doses of macitentan. Furthermore, the active metabolite of macitentan, ACT-132577, demonstrated a longer elimination half-life (approximately 48 hr). Area under the plasma concentration-time curve (AUC) of endothelin-1 was significantly higher in the macitentan 10-mg group compared with the placebo group (exploratory p value, 0.0154). No critical issues regarding the safety and tolerability of macitentan were observed, including time-matched electrocardiographic (ECG) evaluations. The results of this study in healthy Japanese male subjects corroborate with previous studies in Caucasian and Korean subjects. In conclusion, the macitentan dose range from 3 to 10 mg had a good safety and tolerability profile in healthy Japanese male subjects, and its pharmacokinetics and pharmacodynamics were dose-dependent without ethnic differences.