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Healthy male subjects (n\u2009=\u200932) received once daily oral doses of macitentan (1\u2009\u2212\u200930\u2009mg) 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\u2010dose pharmacokinetics of macitentan were dose\u2010proportional and were characterized by a median t<jats:sub>max<\/jats:sub> and apparent elimination half\u2010life varying from 6.0 to 8.5 and 14.3 to 18.5\u2009hours, respectively, for the different doses and minimal accumulation. ACT\u2010132577, a metabolite with lower potency than macitentan, had a half\u2010life of about 48\u2009hours and accumulated approximately 8.5\u2010fold. Compared to placebo, administration of macitentan caused a dose\u2010dependent increase in plasma ET\u20101 with maximum effects attained at 10\u2009mg. A small dose\u2010dependent increase in the 6\u03b2\u2010hydroxycortisol\/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\u20101\u2010dependent pathologies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcph.152","type":"journal-article","created":{"date-parts":[[2013,7,30]],"date-time":"2013-07-30T13:29:05Z","timestamp":1375190945000},"page":"1131-1138","source":"Crossref","is-referenced-by-count":58,"title":["Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple\u2010dose study in healthy subjects"],"prefix":"10.1002","volume":"53","author":[{"given":"Patricia N.","family":"Sidharta","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology Actelion Pharmaceuticals Ltd. Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul L. 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