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.