Lack of Pharmacokinetic Interactions Between Macitentan and a Combined Oral Contraceptive in Healthy Female Subjects

摘要: Macitentan, a dual endothelin receptor antagonist used in pulmonary arterial hypertension, induces cytochrome P450 (CYP) 3A at supratherapeutic concentrations vitro. Most combined oral hormonal contraceptives (OCs) are CYP3A substrates and their efficacy can be affected by inducers. This randomized crossover study assessed possible pharmacokinetic (PK) interactions between macitentan an OC containing ethinyl estradiol norethindrone (or norethisterone). Twenty-six healthy women received single dose of alone (reference) concomitantly with 10 mg steady state (test). No PK interaction was concluded if the 90% confidence intervals (CIs) geometric mean ratios (GMRs; test/reference) peak plasma concentration (Cmax ) exposure from 0 to infinity (AUC0 - ∞ components were within equivalence limits 0.8 1.25. Cmax AUC0-∞ limits. For estradiol, GMRs (90%CIs) 0.92 (0.85-0.99) 0.95 (0.90-0.99). norethindrone, these values 1.02 (0.95-1.09) 1.04 (0.98-1.09), respectively. Overall, treatments well tolerated. major changes baseline safety parameters reported either treatment. Macitentan does not affect OCs.