Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects

Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (C-trough) of macitentan and its active metabolite, ACT-132577, were obtained at steady state in 242 patients, indicating thatmean C-trough of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN. A cross-study comparison showed that although C-trough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (C-max) or area under the plasma concentration-time curve over a dosing interval (AUC(tau)). Geometric mean ratios for C-max and AUC(tau) were 1.08 and 1.22, respectively, for macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.