Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
CEPHA s.r.o., Pilsen, Czech Republic.
Clin Drug Investig. 2023 Nov;43(11):827-837. doi: 10.1007/s40261-023-01310-6. Epub 2023 Oct 19.
The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively.
This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2.
Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated.
A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected.
NCT05480475; date of registration: 29 July, 2022.
双重食欲素受体拮抗剂达理多雷克斯ant 于 2022 年被批准用于治疗失眠症，剂量高达每晚 50 毫克一次。本研究旨在研究达理多雷克斯 ant 50 毫克在稳定状态下对达比加群、达比加群酯的活性部分和瑞舒伐他汀的药代动力学的影响，分别为 P 糖蛋白和乳腺癌耐药蛋白的敏感底物。
这项单中心、开放标签、固定序列研究纳入了 24 名健康男性受试者，他们分别在第 1 天（治疗 A1）和第 9 天（治疗 C1）口服达比加群酯 75 毫克，以及第 3 天（治疗 A2）和第 11 天（治疗 C2）口服瑞舒伐他汀 10 毫克。第 7-14 天，给予达理多雷克斯 ant（50 毫克每日一次）。采集用于两种底物药代动力学和达比加群药效学（即两项凝血试验）的血样，并进行安全性评估。非房室药代动力学参数和药效学变量采用治疗 C1/C2 与 A1/A2 的几何均数比值和 90%置信区间进行评估。
达比加群最大血浆浓度和血浆浓度-时间曲线下面积的几何均数比值（90%置信区间）分别为 1.3（1.0-1.7）和 1.4（1.1-1.9），而最大血浆浓度时间和终末半衰期在两种治疗中相似。药效学变量在两种治疗中均表现出与达比加群药代动力学相似的模式。同时给予达理多雷克斯 ant 时，瑞舒伐他汀的药代动力学没有改变。所有治疗均耐受良好。
在稳定状态下给予达理多雷克斯 ant（50 毫克每日一次）后观察到 P 糖蛋白轻度抑制，而乳腺癌耐药蛋白未受影响。
NCT05480475；注册日期：2022 年 7 月 29 日。
