Lack of pharmacokinetic interaction between the dual endothelin receptor antagonist macitentan and the combined oral contraceptive, norethisterone and ethinyl estradiol

Background: Macitentan is a dual endothelin receptor antagonist (ERA) approved for the long‐term treatment of pulmonary arterial hypertension. ERAs have been associated with teratogenicity and are contraindicated during pregnancy. Hormonal contraceptives (HCs) are cytochrome P450 (CYP) 3A4 substrates and their efficacy can be affected by CYP3A4 inducers. At supra‐therapeutic concentrations, macitentan induced CYP3A4 in vitro. Purpose: To evaluate the effect of macitentan 10 mg (therapeutic dose) in healthy women on the pharmacokinetics (PK) of a combined oral HC, containing 35 mug ethinyl estradiol (EE) and 1 mg norethisterone (NE), and to investigate the safety and tolerability of macitentan co‐administered with this HC. Methods: This open‐label, randomized, two‐way cross‐over study included 26 subjects who received a single oral dose of the HC alone (reference) then concomitantly with macitentan at steady state (test), or vice versa, with a washout period of at least 3 weeks in between. PK, adverse events (AEs), vital signs (VS), electrocardiogram (ECG) variables, and clinical laboratory tests were monitored. No PK interaction was concluded if the 90% confidence intervals (CIs) of geometric mean ratios (test/reference) of the peak plasma concentration (Cmax) and the area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐) of EE and NE were within the bioequivalence criteria of 0.8 to 1.25. Results: All 26 subjects were randomized; mean age was 32.5 years (range 23‐45) and mean body mass index was 24.2 kg/m2. All subjects were included in the safety analyses and 23 subjects were evaluable for the PK analyses. Cmax and AUC0‐ of the HC were within the bioequivalence criteria. For EE, geometric mean ratios (90% CIs) of Cmax and AUC0‐ were 0.92 (0.85, 0.99) and 0.95 (0.90, 0.99), respectively. These values of NE were 1.02 (0.95, 1.09) and 1.04 (0.98, 1.09), respectively. Overall, the HC, macitentan, and the HC co‐administered with macitentan were well tolerated. The most frequently reported AE was headache (69%). One serious AE (asthma bronchiale), assessed as unrelated to macitentan by the investigator, was reported 14 days after last macitentan administration. All AEs resolved without sequelae. No major changes from baseline in VS, ECG variables, and clinical laboratory tests were reported. Conclusions: No PK interactions between macitentan and the HC were observed. Based on this study, the efficacy and safety of HCs are not affected by macitentan co‐administration. In line with previous clinical results, macitentan 10 mg does not affect the PK of CYP3A4 substrates.