title: Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects.
abstract: OBJECTIVE
  Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of pulmonary arterial hypertension (PAH). Warfarin, an anticoagulant often prescribed to patients with PAH, has a narrow therapeutic index and is prone to potential interactions with drugs. This study assessed the effects of macitentan on the pharmacokinetics and pharmacodynamics of single-dose warfarin in healthy subjects.
  
  
  METHODS
  This was a randomised, open-label, single-centre, two-way crossover (treatment A followed by treatment B, or vice versa), phase I study in 14 healthy male subjects. Treatment A was a loading dose of macitentan 30 mg on Day 1 followed by 10 mg once daily for 8 days, with a single 25 mg dose of warfarin on Day 4. Treatment B was a single dose of warfarin on Day 1. Blood samples were assessed for warfarin pharmacokinetics (R- and S-warfarin) and pharmacodynamics [international normalised ratio (INR) and factor VII]. Plasma trough concentrations of macitentan and its active metabolite (ACT-132577) and the safety and tolerability of each treatment were also assessed.
  
  
  RESULTS
  Plasma concentrations of R- and S-warfarin were similar in both treatment periods. Warfarin did not affect the mean trough plasma concentrations of macitentan or ACT-132577. Macitentan did not affect the pharmacodynamics of warfarin; the mean INR and factor VII activity versus time profiles were similar with and without macitentan.
  
  
  CONCLUSIONS
  The absence of effect of macitentan on the pharmacokinetics and pharmacodynamics of a single dose of warfarin suggests that both drugs can be concomitantly administered without need for dose adjustment.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil, Switzerland.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.forename: Hartmut
authors.initials: H
authors.lastname: Dietrich
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065128:Endothelin Receptor Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014859:Warfarin / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D014859:Warfarin; C533860:macitentan