The AAPS Journal

, Volume 14, Issue 1, pp 68–78

Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist


    • Clinical PharmacologyActelion Pharmaceuticals Ltd
  • Päivi Äänismaa
    • Preclinical Pharmacokinetics and MetabolismActelion Pharmaceuticals Ltd
  • Marie-Claude Homery
  • Stephanie Häusler
    • Preclinical Pharmacokinetics and MetabolismActelion Pharmaceuticals Ltd
  • Kyle Landskroner
    • Preclinical Pharmacokinetics and MetabolismActelion Pharmaceuticals Ltd
  • Patricia N. Sidharta
    • Clinical PharmacologyActelion Pharmaceuticals Ltd
  • Alexander Treiber
    • Preclinical Pharmacokinetics and MetabolismActelion Pharmaceuticals Ltd
  • Jasper Dingemanse
    • Clinical PharmacologyActelion Pharmaceuticals Ltd
Research Article

DOI: 10.1208/s12248-011-9316-3

Cite this article as:
Bruderer, S., Äänismaa, P., Homery, M. et al. AAPS J (2012) 14: 68. doi:10.1208/s12248-011-9316-3


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 (AUCτ) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUCτ of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUCτ 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.


cyclosporine (Cs)endothelinmacitentanpharmacokineticsrifampin

Copyright information

© The Author(s) 2011