Luffer-Atlas Debra, Wilbraham Darren, Posada Maria M, Landry John, Tsai Max, Pearlman Eric M
Eli Lilly and Company, Indianapolis, IN, USA.
Eli Lilly and Company, Bracknell, UK.
J Clin Pharmacol. 2024 Jan;64(1):94-102. doi: 10.1002/jcph.2328. Epub 2023 Aug 24.
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 aged 21-70 years with a body mass index of 18.5-35.0 kg/m . 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: a single dose of probe substrate administered on day -2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co-administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co-administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least-squares (LS) mean ratios of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC ) and maximum observed drug concentration (C ) were not contained within the non-effect boundaries (0.80 to 1.25). Dabigatran AUC increased by 25% and C increased by 22%. The median time of maximum observed drug concentration (t ) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co-administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC and C were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC increased by 15% and C increased by 7%. The median t 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.
拉米地坦是P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）外排转运体的体外抑制剂。我们旨在证实基于生理药代动力学模型对拉米地坦的预测，并评估瑞舒伐他汀和达比加群与拉米地坦联合给药的安全性和耐受性。在这项开放标签的上市后药物相互作用1期临床试验中，符合条件的参与者为年龄在21至70岁之间、体重指数为18.5至35.0kg/m²的成年人。第1部分（P-gp，150mg达比加群酯与200mg拉米地坦）和第2部分（BCRP，10mg瑞舒伐他汀与200mg拉米地坦）采用了相似的设计：在第-2天给予单剂量的探针底物并进行药代动力学评估；1周的洗脱期；在第8天和第9天单独给予拉米地坦；在第10天给予拉米地坦并与单剂量的探针底物联合给药，同时对探针底物和拉米地坦进行药代动力学评估。第1部分纳入了66名参与者，第2部分纳入了30名参与者。达比加群与拉米地坦联合给药后，与单独使用达比加群相比，从时间0外推至无穷大的血浆浓度-时间曲线下面积（AUC）和最大观察药物浓度（Cmax）的几何最小二乘（LS）均值比的90%置信区间未包含在无效应边界（0.80至1.25）内。达比加群的AUC增加了25%，Cmax增加了22%。达比加群的最大观察药物浓度（tmax）中位数为2.0至3.0小时。瑞舒伐他汀与拉米地坦联合给药后，与单独使用瑞舒伐他汀相比，AUC和Cmax的几何LS均值比的90%置信区间包含在无效应边界（0.80-1.25）内。瑞舒伐他汀的AUC增加了15%，Cmax增加了7%。瑞舒伐他汀的tmax中位数为4.0小时。结果表明，拉米地坦对P-gp底物有较弱的影响，对BCRP底物无临床相关影响。
