title: Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment.
abstract: Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10 mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC∞) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC∞ of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lindegger
authors.forename: Ivan
authors.initials: I
authors.lastname: Ulč
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000328:Adult; D000368:Aged; D065128:Endothelin Receptor Antagonists / Q000097:blood* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011743:Pyrimidines / Q000097:blood* / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy; D013449:Sulfonamides / Q000097:blood* / Q000627:therapeutic use*
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan
keywords: endothelin receptor antagonist; hepatic function impairment; macitentan; pharmacokinetics; renal function impairment