高变异药物硫酸氢氯吡格雷片的人体生物等效性及饮食影响

Bioequivalence of Highly Variable Drug Clopidogrel Bisulfate and Food Effects on Its Pharmacokinetics

目的评价空腹和餐后服用两种硫酸氢氯吡格雷片的生物等效性,考察饮食对氯吡格雷在中国人体内的药动学影响。方法针对氯吡格雷的高变异性,根据文献报道的该药的个体内变异系数等数据计算空腹给药试验所需受试者例数为70例;根据空腹试验的结果计算餐后给药生物等效性试验所需受试者例数为56例。两次试验分别采用健康男性受试者进行双周期双交叉(清洗期为7 d)单次口服受试制剂和参比制剂300 mg的试验方法。结果空腹口服受试制剂与参比制剂后,氯吡格雷的ρmax分别为(5.78±4.93)、(6.17±6.76)ng·mL-1,tmax分别为(0.71±0.33)、(0.76±0.40)h,AUC0-30 h分别为(8.83±6.72)、(9.35±7.93)ng·h·mL-1,相对生物利用度为(107.3±50.5)%;餐后口服受试制剂与参比制剂后,氯吡格雷的ρmax分别为(30.9±12.5)、(30.1±13.3)ng·mL-1,tmax分别为(1.9±0.6)、(1.9±0.6)h,AUC0-30h分别为(65.0±21.6)、(65.8±22.3)ng·h·mL-1,相对生物利用度为(102.0±23.1)%。两种硫酸氢氯吡格雷片之间在空腹和高脂餐给药后药动学参数均无显著差异(P>0.05)。结论对高变异药物氯吡格雷的生物等效性样本量设计合理。受试制剂和参比制剂在空腹给药和高脂餐后给药情况下均具有生物等效性。与空腹给药相比,高脂餐后给药,tmax延后1.2 h,ρmax和AUC0-30 h分别增大5倍和7倍左右。

OBJECTIVE To investigate the bioequivalence of clopidogrel bisulfate under fasting and fed conditions and the effect of food on the pharmacokinetics of clopidogrel in chinese volunteers. METHODS Based on the high variability of clopidogrel and its intra-subject variation coefficient data reported in the literatures, the sample size of the bioequivalence evaluation of clopidogrel tablets under fasting condition was estimated and designed to 70 subjects. Based on the fasting test results, the sample size of the bioequiva- lence evaluation of clopidogrel tablets in fed condition was designed to 56 subjects. Both of the studies were designed to the open, ran- domized and crossover tests in which a single oral dose of 300 mg clopidogrel bisulfate tablets was administered to healthy male volun- teers. RESULTS The pharmacokinetic parameters of clopidogrel in fasting condition for the test and reference tablets were as follows ： ρmax （5.78±4. 93）vs. （6. 17±6. 76）ng·mL-＇ ,tmax （0. 71 ±0. 33 ） vs. （0. 76±0. 40） h, AUC0-3oh （8. 83 ± 6. 72） vs. （9. 35 ± 7.93 ） ng·h·mL^-1 , and the relative bioavailability of clopidogrel was （ 107.3 ± 50. 5 ） % ; the pharmacokinetic parameters for the test and reference tablets in fed state were as follows -＇Pmax （ 30. 9 ± 12. 5 ） VS. （ 30. 1 ± 13. 3 ）ng·mL- 1, tmax （ 1. 9 ± 0. 6 ） VS. （ 1. 9 ± 0. 6 ） h, AUCo-30 h （ 65. 0 ± 21. 6 ） VS. （ 65. 8 ± 22. 3 ）ng · h · mL^- 1, and the relative bioavailability was （ 102. 0 ± 23. 1 ） %. There were no signif- icant differences in pharmaeokinetic parameters between two tablets （ P 〉 0. 05 ）. CONCLUSION The sample size is reasonably de- signed for the bioequivalence of highly variable drug clopidogrel tablets. The test and reference tablets are considered bioequivalent in human. The pin, and AUC0-30 h increase 5-fold and 7-fold, and tind increase 1.2 h in fed condition compared to the fasting condition.