title: Macitentan: entry-into-humans study with a new endothelin receptor antagonist.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The pharmacokinetic and tolerability profile of macitentan is consistent with a once-a-day dosing regimen and warrants further investigation in clinical studies.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland. patricia.sidharta@actelion.com
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.forename: Paul L M
authors.initials: PL
authors.lastname: van Giersbergen
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010919:Placebos; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan