title: Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist.
abstract: Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent.
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. shirin.bruderer@actelion.com
authors.forename: Shirin
authors.initials: S
authors.lastname: Bruderer
authors.forename: Päivi
authors.initials: P
authors.lastname: Aänismaa
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Homery
authors.forename: Stephanie
authors.initials: S
authors.lastname: Häusler
authors.forename: Kyle
authors.initials: K
authors.lastname: Landskroner
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000328:Adult; D000818:Animals; D019540:Area Under Curve; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D006801:Humans; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C572763:ACT-373898; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D027361:Organic Anion Transporters; D011743:Pyrimidines; D013449:Sulfonamides; D016572:Cyclosporine; C572762:aprocitentan; D012293:Rifampin; C533860:macitentan