硫酸氢氯吡格雷片人体相对生物利用度和生物等效性的评价

摘要

目的 考察硫酸氢氯吡格雷片受试制剂和参比制剂的人体相对生物利用度,并评价两者的生物等效性.方法 32名健康男性志愿者随机交叉单剂量口服硫酸氢氯吡格雷片的受试制剂和参比制剂75 mg,用LC-MS/MS法测定给药后血浆样本中氯吡格雷酸的浓度,用DAS软件计算其药代动力学参数,并评价两种制剂的相对生物利用度及生物等效性.结果 测定人血浆中氯吡格雷酸的线性范围是10～7 000 ng/mL,定量下限为10 ng/mL;氯吡格雷酸和内标氯吡格雷酸-d4的平均提取回收率分别为88.1％和89.6％；批内、批间RSD均小于8.0％,RE在(±8.0％)以内.受试制剂和参比制剂的AUC0-t分别为(11 235.17±2 250.63)ng·h/mL和(10 835.07士1 994.46)ng·h-1·mL-1,AUC0-∞分别为(11 606.80士2 323.53)ng·h-1·mL-1和(11 201.94±1 953.69)ng·h-1 ·mL-1,Cmax分别为(4 724.07±1 399.60)ng/mL和(4 621.96±1 193.52)ng/mL,Tmax分别为(0.68±0.15)h和(0.70±0.23)h,t1/2分别为(8.21±3.26)h和(8.00±1.44)h.受试制剂的相对生物利用度F0-t和F0-∞分别为(103.7士9.6)％、(103.4±8.4)％.结论 两种制剂的吸收速度和吸收程度相当,具有生物等效性.%Objective To evaluate the relative bioavailability and bioequivalence of two clopidogrel hydrogen sulfate tablets in healthy volunteers.Methods A single oral dose of 76 mg clopidogrel hydrogen sulfate test and reference tablets were given to 32 healthy male volunteers in a randomized,two-way crossway study.Clopidogrel acid concentrations in plasma were determined by LC-MS/MS.With use of DAS software,the pharmacokinetic parameters were calculated and the bioequivalence of the two preparations was evaluated.Results Clopidogrel acid was linear in the range of 10-7 000 ng/mL,with the lower of quantification of 10 ng/mL.The average recovery of clopidogrel acid and internal standard clopidogrel acid-d4 were 88.1％ and 89.6 ％,respectively.Both intra-and inter-batch RSD were lower than 8.0％,and RE was within ±8.0％.The main pharmacokinetic parameters of test and reference preparations were as follows:AUC0-t(11 235.17±2 250.63) ng · h-1 · mL-1 and (10 835.07±1 994.46) ng · h 1 · mL-1,AUC0-∞(11 606.80±2 323.53) ng· h-1 ·mL-1 and (11 201.94±1 953.69) ng· h-1 · mL 1,Cmax(4 724.07±1 399.60) ng/mL and (4 621.96±1 193.52) ng/mL,Tmax(0.68±0.15) h and (0.70±0.23) h;t1/2 were (8.21±3.26) h and (8.00±1.44) h,respectively.The F0-t and F0-∞ of test tablet were (103.7±9.6)％ and (103.4±8.4)％,respectively.Conclusion The absorption rate and extent of the two preparations are comparative,and the two preparations are bioequivalent.