低剂量盐酸二甲双胍片餐后生物等效性试验

Bioequivalence of two formulations of low-dose metformin hydrochloride tablets under postprandial condition

目的:研究餐后状态下单次口服受试制剂盐酸二甲双胍片与参比制剂盐酸二甲双胍片在健康受试者体内的药动学及其生物等效性。观察2种制剂在健康受试者中的安全性。方法:入选36例健康受试者,随机分成2组,每组各18例,进食高脂餐后单次口服受试制剂或参比制剂,于给药0 h(进餐结束后、给药前)和给药后1,2,2.5,3,3.5,4,4.5,5,5.5,6,7,8,10,12和24 h采集血样,检测血浆二甲双胍浓度。本项试验为两周期、交叉给药,清洗期为7 d。采用Phoenix^(TM)WinNonlin■8.1软件进行非房室模型药动学参数估算,采用SAS9.4软件进行统计描述与生物等效性评价分析。如果受试制剂与参比制剂的主要药动学参数(C_(max),AUC_(0~t),AUC_(0~∞))几何均值比的90%置信区间均在80.00%~125.00%等效区间内,则证明两制剂生物等效。结果:36例受试者中有1例因不良事件脱落。受试制剂与参比制剂的主要药动学参数:C_(max)分别为(418.42±94.72)和(399.52±79.49)ng·mL^(-1),AUC_(0~t)分别为(3402.04±803.32)和(3219.06±704.13)ng·h·mL^(-1);AUC_(0~∞)分别为(3458.50±815.42)和(3276.11±715.12)ng·h·mL^(-1);二者C_(max)和AUC_(0~t),AUC_(0~∝)几何均值比及其90%置信区间分别为103.11%(98.69%~107.72%),104.73%(100.11%~109.57%)和104.63%(100.03%~109.44%),均在80.00%~125.00%的生物等效区间内。试验过程中未发生严重不良事件和非预期不良事件。结论:受试制剂与参比制剂在中国健康受试者餐后单次口服给药条件下具有生物等效性,2种制剂安全性和耐受性好。

Objective:To study the pharmacokinetics of metformin hydrochloride tablets(manufactured by Beijing Zhongxin Pharmaceutical Co.,Ltd.)and the reference preparation metformin hydrochloride tablets(trade name:Glycoran■,manufactured by Nippon Shinyaku Co.,Ltd.,Japan)in healthy subjects after single-dose administration under postprandial state,evaluate their bioequivalence,and observe the safety.Methods:Thirty-six healthy subjects were randomly divided into two groups,18 in each group.After having high-fat meal,the subjects took the test or reference preparations.Blood samples were collected at 0 h(after meal and before administration)and at 1,2,2.5,3,3.5,4,4.5,5,5.5,6,7,8,10,12 and 24 h after administration.Plasma levels of metformin were measured.The trial consisted of two periods of cross administration and 7-day washout period.Phoenix^(TM) WinNonlin■ 8.1 software was used to estimate the non-compartmental pharmacokinetic parameters,and SAS9.4 software was used for statistical description and bioequivalence analysis.If the 90%confidence interval of geometric mean ratio of main pharmacokinetic parameters(C_(max),AUC_(0-T),AUC_(0~∞))of T/R were within 80.00%~125.00%equivalent interval,it was safely proved that the two preparations were bioequivalent.Results:One out of 36 subjects dropped-out due to adverse events.The main pharmacokinetic parameters of the test and reference preparations were as follows:Cmaxwere(418.42±94.72)and(399.52±79.49)ng·mL^(-1),AUC_(0-t)were(3402.04±803.32)and(3219.06±704.13)ng·h·mL^(-1);AUC_(0~∞)(3458.50±815.42)and(3276.11±715.12)ng·h·mL^(-1).The geometric mean ratios of C_(max),AUC_(0-t),AUC_(0~∝),and their 90%confidence intervals were 103.11%(98.69%~107.72%),104.73(100.11%~109.57%),and 104.63%(100.03%~109.44%),respectively.All were within the bioequivalent range of 80.00%~125.00%.No serious adverse events and unexpected adverse events occurred during the trial.Conclusion:The test preparation is bioequivalent to the reference preparation after a single-dose oral administration under postprandial condition in healthy Chinese subjects.The two preparations have good safety and tolerability.