Pharmacokinetics and safety of concomitant macitentan and hormonal contraceptives

Background: Macitentan, a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension, induces cytochrome P450 (CYP) 3A4 at supra-therapeutic concentrations in vitro. Hormonal contraceptives (HCs) are CYP3A4 substrates and their efficacy can be affected by CYP3A4 inducers. Aim: To evaluate the effect of macitentan on the pharmacokinetics (PK) of a combined HC, ethinyl estradiol 35 μg (EE) and norethisterone 1 mg (NE), and safety and tolerability of concomitant use. Methods: In this randomized, cross-over study, 26 healthy women received a single oral dose of HC alone (reference) and concomitantly with 10 mg macitentan at steady state (test), with a washout of 3 weeks. PK, adverse events (AEs), and safety were monitored. 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 area under the plasma concentration-time curve from 0 to infinity (AUC0 –∞ ) of EE and NE were within the bioequivalence limits of 0.8 to 1.25. Results: Cmax and AUC0-∞ of the HC were within the bioequivalence limits. For EE, GMRs (90% CIs) of Cmax and AUC0-∞were 0.92 (0.85, 0.99) and 0.95 (0.90, 0.99). These values for NE were 1.02 (0.95, 1.09) and 1.04 (0.98, 1.09), respectively. Overall, study treatments were well tolerated. The most frequently reported AE was headache (69%). One unrelated serious AE (asthma bronchiale) was reported. All AEs resolved without sequelae. No major changes from baseline in safety parameters were reported. Conclusions: Macitentan does not affect the PK of the combined HC. In line with previous clinical data, the PK of CYP3A4 substrates are not affected by macitentan.