Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany.
Br J Clin Pharmacol. 2012 Sep;74(3):490-500. doi: 10.1111/j.1365-2125.2012.04218.x.
This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.
This 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 2-8, and single doses of dabigatran etexilate on days 9, 16 and 23.
Twenty-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 concentration-time curve (AUC(0-∞)) 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-∞) 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-∞) 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.
Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.
本研究旨在考察 CYP3A/P-糖蛋白诱导剂利福平对前药达比加群酯口服给药后达比加群药代动力学的影响。
这是一项在健康志愿者中进行的开放标签、固定序列、四周期研究。受试者在第 1 天接受单次达比加群酯 150mg 剂量，第 2-8 天每天接受利福平 600mg 剂量，第 9、16 和 23 天接受单次达比加群酯剂量。
共有 24 名受试者接受了治疗，其中 22 名受试者完成了所有治疗。与参比（单独单次给予达比加群酯；治疗 A）相比，给予达比加群酯前 7 天给予利福平（治疗 B）使总达比加群的几何均数（gMean）AUC（0-∞）和 C（max）分别降低了 67%和 65.5%。达峰时间和终末半衰期不受影响。主要比较（治疗 B 与治疗 A）的 gMean 比值为 33.0%（90%置信区间 26.5%，41.2%），AUC（0-∞）和 34.5%（90%置信区间 26.9%，44.1%），表明总达比加群暴露量有显著影响（总药效达比加群代表非结合达比加群和达比加群葡萄糖醛酸苷的总和）。经过 7 天（治疗 C）或 14 天洗脱（治疗 D）后，与治疗 A 相比，达比加群的 AUC（0-∞）和 C（max）分别降低了 18%和 20%，降低了 15%和 20%，认为无临床意义。所有治疗的总体安全性状况良好。
利福平治疗 7 天可显著降低达比加群的生物利用度，停药 7 天后几乎恢复至基线水平。
