Investigation of the Effects of Ketoconazole on the Pharmacokinetics of Macitentan, a Novel Dual Endothelin Receptor Antagonist, in Healthy Subjects

Macitentan is a potent, orally active, non-peptide antagonist of endothelin receptors with tissue-targeting properties, currently undergoing clinical development for the treatment of pulmonary arterial hypertension. The formation of its active metabolite, ACT-132577, as well as overall elimination of the drug, is catalyzed by the cytochrome P450 (CYP) system, predominantly CYP3A4 and to a lesser extent CYP2C19 isoenzyme. Macitentan is not a substrate of P-glycoprotein. Hepatic uptake is mostly driven by passive diffusion and is not dependent on organic anion-transporting polypeptide transport. This study aimed to investigate the magnitude of a possible effect of a potent CYP3A4 inhibitor, ketoconazole, on the pharmacokinetics of macitentan. In a two-period, randomized, open-label, crossover study, 10 healthy subjects received each of the following treatments: Treatment A in which a single oral dose of 10 mg macitentan was administered on day 1 and Treatment B which consisted of initial daily treatment with ketoconazole 400 mg for 4 days, coadministration of macitentan and ketoconazole on the fifth day and continued administration of ketoconazole for 19 additional days. In the presence of ketoconazole, the exposure to macitentan expressed as area under the plasma concentration-time curve was increased by approximately a factor of 2 and to ACT-132577 was reduced by approximately 26 %. Macitentan was well-tolerated with or without ketoconazole in this study and no relevant differences in safety parameters between the treatments were observed. Although macitentan metabolism is indeed affected by CYP3A4 inhibition, the changes are not considered to be clinically significant and macitentan can be administered concomitantly with CYP3A4 inhibitors without need for dose adjustment.