盐酸二甲双胍缓释片健康人体生物等效性评价

目的:研究盐酸二甲双胍缓释片0.5 g·片-1在健康人体的药动学特征,并对2种制剂的生物等效性进行评价。方法:空腹/餐后各36名健康受试者口服盐酸二甲双胍缓释片受试制剂和参比制剂(Glucophage^■XR^■),采用随机、开放、两周期、两交叉空腹/餐后状态下生物等效性试验。研究采用已验证的液相色谱-串联质谱法作为测定人血浆中二甲双胍浓度的分析方法,测定服药后48 h共14个时间点的血药浓度,计算药动学参数。结果:受试者空腹状态下口服受试制剂和参比制剂后,以二甲双胍的C_max评价受试制剂与参比制剂的生物等效性,C_max的几何均值比值为101.12%,90%CI为94.68%~108.00%,个体内变异为16.36%。AUC_0-t的几何均值比值为100.18%,90%CI为95.13%~105.51%,个体内变异为12.85%;AUC_0-∞的几何均值比值为101.06%,90%CI为95.86%~106.54%,个体内变异为13.11%。受试者餐后状态下口服受试制剂和参比制剂后,C_max的几何均值比值为94.45%,90%CI为90.13%~98.97%,个体内变异为11.39%;以二甲双胍的AUC评价受试制剂与参比制剂的生物等效性,AUC_0-t的几何均值比值为103.21%,90%CI为100.27%~106.24%,个体内变异为7.04%;AUC_0-∞的几何均值比值为103.24%,90%CI为100.31%~106.26%,个体内变异为7.01%。结论:2种制剂在空腹/餐后状态下均具有生物等效性,液相色谱-串联质谱(LC-MS/MS)法准确快速,为临床安全用药提供理论参考。

Bioequivalence of metformin hydrochloride sustained release tablets in healthy human conditions

Objective:To study the pharmacokinetic characteristics of metformin hydrochloride sustainedrelease tablets (0.5 g/tablet) in healthy volunteers,and to evaluate the bioequivalence of the two preparations.Methods:A randomized,open,double-period,double-crossover trial was conducted.The tested reagent and reference reagent (Glucophage^■XR^■) for oral metformin hydrochloride sustained release tablets were applied to 36healthy subjects in fasting/fed state.In this clinical trial,the validated HPLC/tandem mass spectrometry method was used to determine the concentration of metformin in human plasma of 14 time intervals in 48 h.The pharmacokinetic parameters were calculated.Results:After the volunteers were given tested and reference preparations in fasting/fed state,bioequivalence was evaluated by C_maxof metformin.The geometric mean ratio of C_maxwas 101.12%,the90%CI was 94.68%~108.00%,and the intra-individual variation was 16.36%.The geometric mean ratio of AUC_0-twas 100.18%,the 90%CI was 95.13%~105.51%,and the intra-individual variation was 12.85%.The geometric mean ratio of AUC_0-∞ was 101.06%,90%CI was 95.86%~106.54%,and intra-individual variation was 13.11%.The geometric mean ratio of C_maxwas 94.45%,the 90%CI was 90.13%~98.97%,and the intraindividual variation was 11.39%.When the AUC of metformin was used to evaluate the bioequivalence of the tested and reference preparations,the geometric mean ratio of AUC_0-twas 103.21%,the 90%CI was 100.27%~106.24%,and the intra-individual variation was 7.04%.The geometric mean ratio of AUC_0-∞was 103.24%,90%CI was100.31%~106.26%,and intra-individual variation was 7.01%.Conclusion:Both preparations were bioequivalent in fasting/postprandial status.The liquid chromatography-tandem mass spectrometry (LC-MS/MS) used in this study was accurate,rapid,sensitive and precise,providing theoretical reference for clinical safe drug use.