Pharmacokinetic-pharmacodynamic relationships of macitentan, a new endothelin receptor antagonist, after multiple dosing in healthy Korean subjects.

BACKGROUND AND OBJECTIVES: Macitentan is a novel dual endothelin (ET)-1 receptor antagonist to be used in patients with pulmonary arterial hypertension. This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan after administration of multiple doses to healthy Korean male subjects. METHODS: A randomized, double-blind, placebo-controlled, multiple-ascending dose study was performed in 30 healthy male subjects receiving oral macitentan (3, 10, or 30 mg) or placebo once daily for 10 days. Plasma concentrations of macitentan, its active metabolite ACT-13277, and ET-1 were evaluated. Safety and tolerability measurements were conducted throughout the study. RESULTS: The concentration-time profile of macitentan was characterized by slow absorption (median time to maximum plasma concentration [t(max)] 9-10 h) and slow elimination (mean elimination half-life [t ½] 11-15 h). After repeated doses of 3, 10, and 30 mg of macitentan over the course of 10 days, the peak concentration (C(max)) increased as the dose increased and the area under the plasma concentration-time curve during the dosing interval (AUC(τ)) increased in a dose-proportional manner. Plasma concentrations showed approximately 1.5- to 1.9-fold accumulation on day 10 compared with day 1. ACT-132577 showed higher levels of exposure than macitentan, its mean half-life was 46-48 h, and it accumulated 7- to 12-fold. Macitentan increased plasma ET-1 concentrations at all doses tested and was well tolerated and elicited no serious adverse events. CONCLUSION: Multiple oral doses of 3, 10, and 30 mg of macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations.