Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 53, Issue 11, Pages 1131-1138Publisher
WILEY
DOI: 10.1002/jcph.152
Keywords
macitentan; endothelin receptor antagonist; healthy subjects; pharmacokinetics; pharmacodynamics
Categories
Funding
- Actelion Pharmaceuticals Ltd.
Ask authors/readers for more resources
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 (1-30mg) 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 t(max) and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48hours 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 10mg. A small dose-dependent increase in the 6-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available