Zibotentan Can Be Co‐administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug–Drug Interaction Study

Abstract

The endothelin A receptor antagonist zibotentan, combined with the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single‐sequence, within‐participant comparison study was conducted in 24 healthy women of non‐childbearing potential, comparing the PK of ethinyl estradiol/levonorgestrel alone and with zibotentan. Single oral doses of 0.06 mg ethinyl estradiol/0.3 mg levonorgestrel were administered on Days 1 and 15; zibotentan 10 mg was dosed orally, once‐daily through Days 6–19. PK profiles were determined and ethinyl estradiol/levonorgestrel PK was compared between Day 1 and 15 based on geometric least‐squares mean ratios of PK parameters, including maximum observed concentration (Cmax) and area under the plasma concentration–time curve from zero to infinity (AUCinf). Co‐administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] Cmax 1.05 [0.99–1.11], AUCinf 1.00 [0.96–1.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (Cmax 1.12 [1.02–1.23], AUCinf 1.30 [1.21–1.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol/levonorgestrel was not reduced by multiple‐dose zibotentan. In conclusion, contraception containing ethinyl estradiol/levonorgestrel is regarded possible under zibotentan‐containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.