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.