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.