Effect of Steady-State Ambrisentan on the Pharmacokinetics of a Single Dose of the Oral Contraceptive Norethindrone (Norethisterone) 1 mg/Ethinylestradiol 35 mu g in Healthy Subjects An Open-Label, Single-Sequence, Single-Centre Study

Background: Ambrisentan is an oral, once-daily endothelin receptor antagonist (ERA) that is approved for the treatment of pulmonary arterial hypertension (PAH). Pregnancy is not recommended for women of childbearing potential with PAH, due to an increased risk of mortality. Additionally, the ERA class is teratogenic in animal studies. A highly effective method of contraception is therefore strongly recommended for women of childbearing potential who are treated with an ERA for PAH. Objective: This study investigated the effect of ambrisentan on the pharmacokinetics (PK) of the oral contraceptive norethindrone (norethisterone) 1 mg/ethinylestradiol 35 mu g (NT 1 mg/EE 35 mu g). Methods: The study was an open-label, single-sequence, PK study designed to assess the effect of multiple doses of ambrisentan (Letairis (R), Volibris (R)) on the PK of a single oral dose of NT 1 mg/EE 35 mu g (Ortho-Novum (R) 1/35) in a single clinical research centre in the US. The study included 28 healthy female subjects in general good health, aged 18-45 years, and who had a body mass index of 18.5-29.9 kg/m(2). A single oral dose of NT 1 mg/EE 35 mu g was administered on day 1. On day 10, following a wash-out period, fasted subjects received once-daily 10 mg doses of ambrisentan for 12 days. On day 22, a single oral dose of NT 1 mg/EE 35 mu g and a single 10 mg oral dose of ambrisentan were coadministered; thereafter, subjects continued to receive once-daily oral doses of ambrisentan 10 mg on days 23 through 26. The primary PK endpoints included maximum observed plasma drug concentration (C-max), time to reach C-max (t(max)), and the area under the plasma concentration-time curve from time zero to the time of last measurable concentration (AUC(last)). Results: Ethinylestradiol C-max was slightly decreased (geometric mean ratio [GMR] 91.7%; 90% CI 86.1, 97.8) and AUC(last) was similar (GMR 99.1%; 90% CI 91.0, 107.9) in the presence of ambrisentan compared with NT 1 mg/EE 35 mu g. Norethindrone C-max (GMR 113.2%; 90% CI 102.4, 125.1) and AUC(last) (GMR 112.9%; 90% CI 104.9, 121.6) were slightly increased in the presence of ambrisentan. The 90% CIs were within the pre-defined no-effect boundaries for all PK parameters, except for the C-max of norethindrone, which was slightly above the upper limit of 125%. No safety concerns were apparent with the coadministration of NT I mg/EE 35 mu g and ambrisentan. Conclusion: No dose adjustment of the oral contraceptive NT 1 mg/EE 35 mu g is warranted with the coadministration of ambrisentan.