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

• Published in: Journal of clinical pharmacology 2017-08, Vol.57 (8), p.997-1004
• Main Authors: Issac, Milena, Dingemanse, Jasper, Sidharta, Patricia N.
• Format: Article
• Language: English
• Subjects: Adult; Aged; comparison; Endothelin A Receptor Antagonists - blood; Endothelin A Receptor Antagonists - pharmacokinetics; Endothelin B Receptor Antagonists - blood; Endothelin B Receptor Antagonists - pharmacokinetics; endothelin receptor antagonist; Familial Primary Pulmonary Hypertension - blood; Familial Primary Pulmonary Hypertension - metabolism; Female; Healthy Volunteers; Humans; macitentan; Male; Middle Aged; patients; Pharmacokinetics; pulmonary arterial hypertension; Pulmonary hypertension; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.888

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 (Ctrough) of macitentan and its active metabolite,  ACT‐132577,  were obtained at steady state in 242 patients, indicating that mean Ctrough 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  A cross‐study comparison showed that although Ctrough in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT‐132577, respectively, this does not translate to a significant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 (Cmax) or area under the plasma concentration–time curve over a dosing interval (AUCτ). Geometric mean ratios for Cmax and AUCτ 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.