Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans

Abstract

1. Macitentan is a tissue-targeting, dual endothelin receptor antagonist, currently under phase 3 investigation in pulmonary arterial hypertension.

2. In this study the disposition and metabolism of macitentan were investigated following administration of a single oral 10 mg dose of ¹⁴C-macitentan to six healthy male subjects.

3. The total radioactivity in matrices was determined using liquid scintillation counting. The proposed structure of metabolites was based on mass spectrometry characteristics and, when available, confirmed by comparison with reference compounds.

4. Mean (± SD) cumulative recovery of radioactivity from faeces and urine was 73.6% (±6.2%) of the administered radioactive dose, with 49.7% (±3.9%) cumulative recovery from urine, and 23.9% (±4.8%) from faeces. In plasma, in addition to parent macitentan, ACT-132577, a pharmacologically active metabolite elicited by oxidative depropylation and the carboxylic acid metabolite ACT-373898 were identified. In urine, four entities were identified, with the hydrolysis product of ACT-373898 as the most abundant one. In faeces, five entities were identified, with the hydrolysis product of macitentan and ACT-132577 as the most abundant one. Concentrations of total radioactivity in whole blood were lower compared to plasma, which indicates that macitentan and its metabolites poorly bind to or penetrate into erythrocytes.

Keywords::

• Mass balance
• metabolite profiling
• pharmacokinetics
• Phase I