Key result
Macitentan (10 mg) did not affect the pharmacokinetics of a combined oral contraceptive in healthy women, with geometric mean ratios for Cmax and AUC remaining within 0.8-1.25 equivalence limits.
Why the study?
Does macitentan alter the pharmacokinetics of a combined oral contraceptive in healthy women?
RCT (n=26)
Crossover
Does macitentan alter the pharmacokinetics of a combined oral contraceptive in healthy women?
Effect estimate: GMRs for ethinyl estradiol Cmax 0.92 and AUC 0.95; norethindrone Cmax 1.02 and AUC 1.04 (95% CI 0.85-0.99, 0.90-0.99, 0.95-1.09, 0.98-1.09 (90% CIs))
Macitentan does not have a clinically significant pharmacokinetic interaction with combined oral contraceptives, suggesting they can be safely co-administered.
Supports safe co-administration of macitentan with combined oral contraceptives without adjustment; confirms absence of pharmacokinetic interaction in this RCT.
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.
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Hurst et al. (2015) conducted an RCT in Healthy (n=26). Macitentan and combined oral contraceptive vs. Combined oral contraceptive alone was evaluated on Pharmacokinetic interactions (Cmax and AUC0-∞ of ethinyl estradiol and norethindrone) (GMRs for ethinyl estradiol Cmax 0.92 and AUC 0.95; norethindrone Cmax 1.02 and AUC 1.04, 95% CI 0.85-0.99, 0.90-0.99, 0.95-1.09, 0.98-1.09 (90% CIs)). Macitentan (10 mg) did not affect the pharmacokinetics of a combined oral contraceptive in healthy women, with geometric mean ratios for Cmax and AUC remaining within 0.8-1.25 equivalence limits.
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