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 (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.

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

“…Our study illustrates how GLB plasma pharmacokinetics and distribution are largely governed by OATP transporters. RFA and CsA have a more pronounced inhibitory effect on OATP1A2, OATP1B1, and OATP1B3 than on OATP2B1 (13,(41)(42)(43)(44). In the present study, the organs in which […”

Macitentan Does Not Interfere with Hepatic Bile Salt Transport

“…These conclusions were confirmed in a clinical drug-drug interaction study with cyclosporin A, an established potent inhibitor of OATP-mediated (Shitara et al, 2003) and NTCP-mediated transport (Mita et al, 2006). Concomitant cyclosporin A increased macitentan exposure in humans by only 1.1-fold (Bruderer et al, 2012a), compared with a 30-fold increase observed with the proven OATP substrate bosentan in the presence of cyclosporin A (Binet et al, 2000).…”

“…We have previously reported on the cellular uptake of macitentan in OATP1B1-and OATP1B3-overexpressing cells in the context of the clinical drug-drug interaction studies with cyclosporin A and rifampicin (Bruderer et al, 2012a). Table 1 summarizes these results of the uptake experiments with macitentan and ACT-132577 together with new data on OATP2B1.…”

Pathways in pulmonary arterial hypertension: the future is here

“…data from phase I studies support a once-daily dosing regimen for macitentan and demonstrate that it can be taken irrespective of food intake and without drug-drug interactions with warfarin, sildenafil, ketoconazole or cyclosporine [20,21].…”