Effect of Steady-State Ambrisentan on the Pharmacokinetics of a Single Dose of the Oral Contraceptive Norethindrone (Norethisterone) 1 mg/Ethinylestradiol 35 μg in Healthy Subjects

Methods: The study was an open-label, single-sequence, PK study designed to assess the effect of multiple doses of ambrisentan (Letairis®; Volibris®) on the PK of a single oral dose of NT 1 mg/EE 35 μg (Ortho-Novum® 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/m². A single oral dose of NT 1 mg/EE 35 μg 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 μg 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 μg. Norethindrone C_max (GMR 113.2%; 90% CI 102.4, 125.1) and AUC[inlast] (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 1 mg/EE 35 μg and ambrisentan.