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.
摘要：
内皮素A受体拮抗剂zibotentan,与钠-葡萄糖协同转运蛋白2抑制剂达格列净联合，正在研究治疗高蛋白尿的慢性肾脏疾病。允许育龄妇女获得这种治疗，需要高度有效的避孕方法，并且必须避免影响避孕可靠性的药物相互作用。这项研究调查了zibotentan与避孕药乙炔基雌二醇和左炔诺孕酮之间的药代动力学（PK）相互作用的风险。单序列，参与者内部比较研究是在24名非生育潜力的健康女性中进行的，比较乙炔雌二醇/左炔诺孕酮单独和与zibotentan的PK。在第1天和第15天给予单次口服0.06mg乙炔雌二醇/0.3mg左炔诺孕酮；口服给药10mgzibotentan，每天一次，直到第6-19天。根据PK参数的几何最小二乘平均比率，确定PK曲线，并在第1天和第15天之间比较乙炔雌二醇/左炔诺孕酮PK。包括最大观察浓度（Cmax）和从零到无穷大的血浆浓度-时间曲线下面积（AUCinf）。与zibotentan共同给药不影响乙炔雌二醇PK（几何平均比[90％置信区间]Cmax1.05[0.99-1.11]，AUCinf1.00[0.96-1.05]),而左炔诺孕酮的相互作用较弱（暴露增加）（Cmax1.12[1.02-1.23]，AUCinf1.30[1.21-1.39]),这被认为没有临床相关性。多剂量zibotentan并未减少乙炔雌二醇/左炔诺孕酮的血浆暴露。总之,在含有zibotentan的治疗中，含有乙炔雌二醇/左炔诺孕酮的避孕药被认为是可能的。这扩大了有生育潜力的妇女的选择，支持ZENITH高蛋白尿试验的多样性。
