2种盐酸二甲双胍缓释片在中国健康受试者空腹单次口服给药条件下的生物等效性和安全性

Bioequivalence and safety of metformin hydrochloride sustainedrelease tablets with single-dose oral administration under fasting conditions in Chinese healthy volunteers

目的研究仿制盐酸二甲双胍缓释片元唐(受试制剂)和原研药格华止缓释片(参比制剂)在中国健康受试者中空腹单次po给药的生物等效性和安全性。方法36例健康受试者在空腹单次po给药(500 mg)后进行随机、开放、两周期、两交叉试验。第1周期给药后,7 d清洗期后进行第2周期交叉给药。每周期给药0 h(给药前30 min内)和给药后36 h内不同时间点采集血样。液相色谱-串联质谱法测定脱蛋白血浆中二甲双胍浓度,用非房室模型计算各受试者的药动学参数并分析生物等效性。采用SAS 9.4软件统计分析2种药物的安全性。结果试验过程中,2例受试者脱落,34例受试者完成试验。受试制剂和参比制剂曲线下面积(AUC)分别为AUC_(0→t)5.3±1.5和(5.1±1.4)h·mg·L^(-1),AUC_(0→∞)5.4±1.5和(5.2±1.4)h·mg·L^(-1),最大血药浓度(C_(max))分别为0.82±0.22和(0.79±0.23)mg·L^(-1);三者的几何均值之比(90%置信区间)分别为103.2%(96.2%~110.8%),103.1%(96.3%~110.4%)和104.6%(96.3%~113.7%),均在生物等效区间(80.0%~125.0%)范围内。方差分析结果显示,给药顺序、给药周期和剂型对受试制剂和参比制剂等效性无显著影响。药物耐受性好,不良事件具有自限性,2种制剂不良反应的发生率、种类、严重程度和转归无显著差异。结论2种盐酸二甲双胍缓释片在中国健康受试者中空腹单次给药条件下生物等效,安全性良好。

OBJECTIVE To study the bioequivalence and safety of generic metformin hydrochlo⁃ride sustained-release tablets Yuantang(the test preparation)and the original metformin hydrochloride extended-release tablets Glucophage XR(the reference preparation)under the conditions of fasting and single-dose oral administration in healthy Chinese volunteers.METHODS A randomized,open,two-period,two-crossover bioequivalence and safety trial was conducted in 36 healthy Chinese volun⁃teers under the conditions of fasting and single oral administration of the test preparation or the refer⁃ence preparation.Cross-administration was carried out during the second period after 7-day washout.Blood samples were collected at different time points from 0 h(within 30 min before administration)to 36 h after administration in each period.The concentrations of metformin in deproteinized plasma were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS).The pharmacokinetic parameters and bioequivalence were calculated by the non-compartment model in Phoenix WinNonlin 7.0 software.The safety results of the two drugs were statistically analyzed with SAS 9.4 software.RESULTS Two subjects dropped out during the trial and the others completed the trial.The area under the curve AUC_(0→t)and AUC0→∞)and the maximum plasma concentration(Cmax)of the test preparation and the reference preparation were AUC_(0→t)5.3±1.5 and(5.1±1.4)h·mg·L^(-1),AUC0→∞5.4±1.5 and(5.2±1.4)h·mg·L^(-1),Cmax 0.82±0.22 and(0.79±0.23)mg·L^(-1),respectively.The geometric mean ratios of AUC_(0→t),AUC0→∞and Cmax(90%confidence interval)were 103.2%(96.2%-110.8%),103.1%(96.3%-110.4%)and 104.6%(96.3%-113.7%),respectively,which were in the range of bioequivalence(80.0%-125.0%).Analysis of variance showed that the sequence of administration,period of adminis⁃tration and drug preparation had no significant effect on the equivalence of the two drugs.The drug was well tolerated and adverse events were self-limiting.There was no significant difference in the inci⁃dence,type,severity or outcome of adverse reactions between the two preparations.CONCLUSION The two preparations of metformin hydrochloride sustained-release tablets are bioequivalent and safe in healthy Chinese volunteers under the conditions of fasting and single-dose oral administration.