title: Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects.
abstract: 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 Ctroughof 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  A cross-study comparison showed that although Ctroughin PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT-132577, respectively, this does not translate to a significant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 Cmaxand AUCτwere 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.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Milena
authors.initials: M
authors.lastname: Issac
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
mesh_terms: D000328:Adult; D000368:Aged; D065130:Endothelin A Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D065131:Endothelin B Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D065627:Familial Primary Pulmonary Hypertension / Q000097:blood / Q000378:metabolism*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C572762:aprocitentan; C533860:macitentan
keywords: comparison; endothelin receptor antagonist; macitentan; patients; pharmacokinetics; pulmonary arterial hypertension