PURPOSE: To study the pharmacokinetics, pharmacodynamics, and tolerability of 
rising single doses of macitentan, an endothelin receptor antagonist, in healthy 
male subjects.
METHODS: This double-blind, placebo-controlled study was performed in seven 
groups of eight healthy male subjects. Doses of 0.2, 1, 5, 25, 100, 300 and 
600 mg or placebo (two subjects per group) were administered. Plasma macitentan 
and endothelin-1 and serum total bile salt concentrations were measured and 
analysed non-compartmentally. Plasma and urine were analysed qualitatively for 
the presence of metabolites and one of these, ACT-132577, was also measured 
quantitatively in plasma. Standard tolerability measurements were performed 
throughout the study.
RESULTS: Macitentan was slowly absorbed and, at a dose of 300 mg, the t(1/2) 
(95% confidence interval, CI) was 17.5 h (14.1, 21.8). The dose-proportionality 
coefficient β for C(max) (95% CI) was 0.83 (0.79, 0.87) indicating less than 
dose-proportional pharmacokinetics of macitentan. In plasma, a pharmacologically 
active oxidative depropyl metabolite, ACT-132577, was found whereas in urine two 
minor metabolites were detected. The t(1/2) of ACT-132577 (95% CI) was 65.6 h 
(53.1, 80.9). Macitentan dose-dependently increased endothelin-1 concentrations 
up to 2.2-fold (95% CI 1.4, 2.4) at a dose of 600 mg, but had no consistent 
effect on total bile salts. Macitentan was well tolerated up to and including a 
dose of 300 mg, the maximum tolerated dose. Headache, nausea and vomiting were 
dose-limiting adverse events.
CONCLUSION: The pharmacokinetic and tolerability profile of macitentan is 
consistent with a once-a-day dosing regimen and warrants further investigation 
in clinical studies.