Lasmiditan是一种体外抑制剂，可抑制P-糖蛋白（P-gp）和乳腺癌抗药性蛋白（BCRP）的外排转运。我们旨在确认激活P-糖蛋白（P-gp）和乳腺癌抗药性蛋白（BCRP）的激动模型对lasmiditan的预测，并评估lasmiditan联合应用rosuvastatin和dabigatran的安全性和耐受性。在这项开放标签、后市场药物相互作用1期临床试验中，合格的参与者为21-70岁之间、身体质量指数为18.5-35.0 kg/m2的成年人。部分1（P-gp：150 mg dabigatran etexilate联合200 mg lasmiditan）和部分2（BCRP：10 mg rosuvastatin联合200 mg lasmiditan）以相似的设计进行：在第-2天给予一次探针底物剂量，并进行药代动力学评估；间隔1周停药；分别在第8天和第9天单独给予lasmiditan；在第10天联合给予一次探针底物剂量，并对探针底物和lasmiditan进行药代动力学评估。部分1包括66名参与者，部分2包括30名参与者。在lasmiditan联合dabigatran与单独给予dabigatran相比后，AUC[0-∞]和Cmax的几何最小二乘均值比值的90％置信区间未包含在不产生效应边界（0.80-1.25）之内。dabigatran的AUC[0-∞]增加了25％，Cmax增加了22％。dabigatran的中位tmax为2.0-3.0小时。在lasmiditan联合rosuvastatin与单独给予rosuvastatin相比后，几何最小二乘均值比值的90％置信区间在不产生效应边界（0.80-1.25）之内。rosuvastatin的AUC[0-∞]增加了15％，Cmax增加了7％。rosuvastatin的中位tmax为4.0小时。结果表明，lasmiditan对P-gp底物的作用较弱，对BCRP底物没有临床相关的影响。本文受版权保护。保留所有权利。

Lasmiditan is an in vitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically-based pharmacokinetic models of lasmiditan and assess the safety and tolerability of rosuvastatin and dabigatran co-administered with lasmiditan. In this open-label, post-marketing drug-drug interaction phase 1 clinical trial, eligible participants were adults 21-70 years old with body mass index 18.5-35.0 kg/m2 . Part 1 (P-gp: 150 mg dabigatran etexilate with 200 mg lasmiditan) and Part 2 (BCRP: 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: single dose of probe substrate administered Day -2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered Days 8 and 9 alone; lasmiditan co-administered with single dose of probe substrate Day 10 with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in Part 1 and 30 in Part 2. Following dabigatran co-administration with lasmiditan vs. dabigatran alone, 90% confidence intervals for geometric least squares (LS) mean ratios of AUC[0-∞] and Cmax were not contained within non-effect boundaries (0.80-1.25). Dabigatran AUC[0-∞] increased by 25% and Cmax by 22%. Median tmax for dabigatran was 2.0-3.0 hours. Following rosuvastatin co-administration with lasmiditan vs. rosuvastatin alone, 90% CIs for geometric LS mean ratios of AUC[0-∞] and Cmax were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC[0-∞] increased by 15% and Cmax by 7%. Median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P-gp substrates and no clinically relevant effect on BCRP substrates. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.