title: Lack of Pharmacokinetic Interactions Between Macitentan and a Combined Oral Contraceptive in Healthy Female Subjects.
abstract: Macitentan, a dual endothelin receptor antagonist used in pulmonary arterial hypertension, induces cytochrome P450 (CYP) 3A at supratherapeutic concentrations in vitro. Most combined oral hormonal contraceptives (OCs) are CYP3A substrates and their efficacy can be affected by CYP3A inducers. This randomized crossover study assessed possible pharmacokinetic (PK) interactions between macitentan and an OC containing ethinyl estradiol and norethindrone (or norethisterone). Twenty-six healthy women received a single oral dose of OC alone (reference) and concomitantly with 10 mg macitentan at steady state (test). No PK interaction was concluded if the 90% confidence intervals (CIs) of geometric mean ratios (GMRs; test/reference) of the peak plasma concentration (Cmax ) and the exposure from 0 to infinity (AUC0 - ∞ ) to the OC components were within the equivalence limits of 0.8 to 1.25. Cmax and AUC0-∞ of the OC were within the equivalence limits. For ethinyl estradiol, GMRs (90%CIs) of Cmax and AUC0-∞ were 0.92 (0.85-0.99) and 0.95 (0.90-0.99). For norethindrone, these values were 1.02 (0.95-1.09) and 1.04 (0.98-1.09), respectively. Overall, study treatments were well tolerated. No major changes from baseline in safety parameters were reported in either treatment. Macitentan does not affect the PK of OCs.
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
authors.forename: Noémie
authors.initials: N
authors.lastname: Hurst
authors.affiliation: ClinPharmCologne, MEDA, Köln, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Pellek
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.affiliation: Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
mesh_terms: D000328:Adult; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004347:Drug Interactions / Q000502:physiology; D065130:Endothelin A Receptor Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D003277:Contraceptives, Oral, Combined; D065130:Endothelin A Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan
keywords: endothelin receptor antagonist; hormonal contraceptives; macitentan; pharmacokinetics