Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin
Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin
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DOI：
10.1111/j.1365-2125.2012.04218.x
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发表时间：
2012-09-01
影响因子：
3.4
通讯作者：
Reilly, Paul A.
中科院分区：
文献类型：
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作者：
Haertter, Sebastian;Koenen-Bergmann, Michael;Reilly, Paul A.
目的本研究探讨了CYP3A/P-糖蛋白诱导剂，利福平，对达比加群的药代动力学口服给药后的前药，dabigatran etexilate.METHODS这是一个开放标签，固定序列，四个阶段的研究在健康志愿者。受试者在第1天接受达比加群酯150 mg单次给药，在第28天接受利福平600 mg每日一次给药，在第9、16和23天接受达比加群酯单次给药。共有24例受试者接受治疗，其中22例接受了所有治疗。与参比药物（达比加群酯单次给药;治疗A）相比，利福平给药7天后达比加群酯给药（治疗B）使总达比加群的浓度-时间曲线下面积（AUC（0-无穷大））和最大血浆浓度（C-max）的几何平均值（gMean）分别降低67%和65.5%。达峰时间和终末半衰期不受影响。主要比较的几何均值比（治疗B vs.治疗A）为33.0% AUC（90%置信区间26.5，41.2%）（0-无穷大）和34.5% C-max（90%置信区间26.9，44.1%），表明对达比加群总暴露量有显著影响（总代谢活性达比加群代表非结合达比加群和达比加群葡糖苷酸的总和）。与治疗A相比，7天（治疗C）或14天洗脱期（治疗D）后，达比加群的AUC（0-无穷大）和C-max分别降低18%和20%以及15%和20%，认为无临床意义。所有治疗的总体安全性是良好的。CONCLUSIONSAgment利福平7天导致达比加群的生物利用度显着降低，7天洗脱后几乎恢复到基线。
AIMSThis study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.METHODSThis was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 28, and single doses of dabigatran etexilate on days 9, 16 and 23.RESULTSTwenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentrationtime curve (AUC(0-infinity)) and maximal plasma concentration (C-max) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC(0-infinity) and 34.5% (90% confidence interval 26.9, 44.1%) for C-max, indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC(0-infinity) and C-max of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good.CONCLUSIONSAdministration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.