A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension.

Background: Macitentan and its active metabolite, aprocitentan, are non-peptide, potent, dual endothelin receptor antagonists. Macitentan is approved for the treatment of pulmonary arterial hypertension in adults, at a dose of 10 mg/day.

Objective: The objective of this study was to develop a comprehensive population model to describe the pharmacokinetics of macitentan and aprocitentan in healthy adults and adult subjects with pulmonary arterial hypertension.

Methods: Pharmacokinetic data of 452 subjects in nine studies, after single and repeated doses (dose range 0.2-600 mg), were pooled for a non-linear mixed-effects analysis and the assessment of covariates, i.e., body weight, age, sex, race, renal and hepatic impairment, health status (healthy volunteers vs patients with pulmonary arterial hypertension), and formulation (capsules vs tablets) on pharmacokinetic parameters.

Results: The final model was an open one-compartment disposition model, with linear elimination for macitentan and linear formation and elimination for aprocitentan. A semi-mechanistic absorption model described the dose dependency and multiple peaks observed for macitentan. For a female patient with pulmonary arterial hypertension after oral administration at 10 mg, macitentan reached a maximum concentration after 9 h and, following daily dosing, reached steady state after 3 days with a twofold accumulation factor. The apparent volume of distribution was 34 L and clearance was 1.39 L/h. Aprocitentan reached maximum concentration after 51 h and steady state after 9 days, with a 12.5-fold accumulation factor. Body weight, sex, race, renal impairment, health status, and formulation were statistically significant covariates on pharmacokinetic parameters.

Conclusions: The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations. Several covariates significantly influenced the pharmacokinetics of macitentan and aprocitentan, but none was considered clinically relevant.