This multiple-ascending-dose study investigated safety, tolerability, 
pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor 
antagonist (ERA) with sustained receptor binding and enhanced tissue penetration 
properties compared to other ERAs. Healthy male subjects (n = 32) received once 
daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. 
Administration of macitentan was safe and well tolerated. Macitentan had no 
effect on bile salts, suggesting an improved liver safety profile. The 
multiple-dose pharmacokinetics of macitentan were dose-proportional and were 
characterized by a median tmax and apparent elimination half-life varying from 
6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and 
minimal accumulation. ACT-132577, a metabolite with lower potency than 
macitentan, had a half-life of about 48 hours and accumulated approximately 
8.5-fold. Compared to placebo, administration of macitentan caused a 
dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A 
small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary 
excretion ratio was observed, although there were no statistically significant 
differences between treatments including placebo. Effects of macitentan on 
cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The 
present results support investigation of macitentan in the management of 
pulmonary arterial hypertension and ET-1-dependent pathologies.