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Lack of Pharmacokinetic Interactions Between Macitentan and a Combined Oral Contraceptive in Healthy Female Subjects
Author(s) -
Hurst Noémie,
Pellek Matthias,
Dingemanse Jasper,
Sidharta Patricia N.
Publication year - 2016
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.639
Subject(s) - cmax , pharmacokinetics , cyp3a , crossover study , medicine , pharmacology , norethisterone , ambrisentan , confidence interval , population , bosentan , placebo , endothelin receptor , cytochrome p450 , receptor , alternative medicine , environmental health , pathology , metabolism , research methodology
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 (C max ) and the exposure from 0 to infinity (AUC 0 – ∞ ) to the OC components were within the equivalence limits of 0.8 to 1.25. C max and AUC 0–∞ of the OC were within the equivalence limits. For ethinyl estradiol, GMRs (90%CIs) of C max and AUC 0–∞ 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.