摘要
目的 评价空腹及餐后状态下单次口服盐酸贝那普利片受试和参比制剂的生物等效性.方法 将志愿者按照 1·1 的比例分配至T-R(受试制剂-参比制剂)和 R-T(参比制剂-受试制剂)序列组;采用单中心、随机、开放、两周期、双序列、自身交叉、单次给药(空腹、餐后)的试验方法设计;采用高效液相-色谱串联质谱法测定血药浓度;使用WinNonlin软件的非房室模型对贝那普利主要药代动力学参数 Cmax、AUC0-t、AUC0-∞进行分析;Tmax采用非参数秩和检验.结果 空腹组受试制剂和参比制剂贝那普利的主要药代动力学参数如下:Cmax分别为(207.86±70.77)ng·mL-1 和(205.20±70.37)ng·mL-1;AUC0-t分别为(168.91±36.03)h×ng·mL-1 和(170.23±38.37)h×ng·mL-1;AUC0-∞分别为(171.01±36.15)h×ng·mL-1 和(172.27±38.49)h×ng·mL-1;Tmax分别为(0.48±0.11)h和(0.49±0.17)h.空腹组受试制剂和参比制剂活性代谢物贝那普利拉的主要药代动力学参数如下:Cmax分别为(270.45±69.07)ng·mL-1 和(271.86±65.90)ng·mL-1;AUC0-t分别为(1 490.10±295.32)h×ng·mL-1 和(1 487.96±285.39)h×ng·mL-1;AUC0-∞分别为(1 535.19±289.52)h×ng·mL-1 和(1 532.63±285.26)h×ng·mL-1;Tmax分别为(1.45±0.47)h 和(1.41±0.33)h.餐后组受试制剂和参比制剂贝那普利的 Cmax分别为(102.05±41.17)ng·mL-1 和(112.04±49.39)ng·mL-1;AUC0-t分别为(149.19±32.76)h×ng·mL-1 和(151.70±33.78)h×ng·mL-1;AUC0-∞分别为(151.02±33.08)h×ng·mL-1 和(154.03±33.99)h×ng·mL-1;Tmax分别为(1.14±0.65)h和(1.09±0.60)h.餐后组受试制剂和参比制剂的活性代谢物贝那普利拉的 Cmax分别为(207.71±50.76)ng·mL-1 和(211.68±66.50)ng·mL-1;AUC0-t分别为(1 366.01±292.24)h×ng·mL-1 和(1343.78±315.41)h×ng·mL-1;AUC0-∞分别为(1 414.95±297.71)h×ng·mL-1 和(1 387.03±314.17)h×ng·mL-1;Tmax分别为(2.46±0.87)h和(2.46±0.85)h.受试制剂与参比制剂贝那普利和贝那普利拉的 Cmax、AUC0-t、AUC0-∞的几何均值比值的 90%置信区间均在 80%～125%;Tmax在两种制剂间差异无统计学意义(P＞0.05).结论 盐酸贝那普利片的受试制剂和参比制剂具有生物等效性.
Abstract
Objective To evaluate the bioequivalence of test and reference preparations after single oral administration of benazepril hydrochloride tablets in healthy subjects under fasting and postprandial conditions.Methods The volunteers were assigned to either T-R(test preparation-reference preparation)or R-T(reference preparation-test preparation)sequence by 1·1 ratio.Sin-gle-center,randomized,open,two-cycle,double-sequence,self-crossover,fasting and postprandial single administration protocols were used for experiment design.The plasma concentrations of benazepril hydrochloride were determined by high performance liquid chromatography-tandem mass spectrometry.The main pharmacokinetic parameters Cmax,AUC0-t and AUC0-∞ were ana-lyzed using the non-atrioventricular mode of WinNonlin.Tmax was analyzed by nonparametric rank sum test.Results The Cmax,AUC0-t,AUC0-∞and Tmax of benazepril test and reference prepara-tions in the fasting group were(207.86±70.77)ng·mL-1 and(205.20±70.37)ng·mL-1,(168.91±36.03)h×ng·mL-1 and(170.23±38.37)h×ng·mL-1,(171.01±36.15)h×ng·mL-1 and(172.27±38.49)h×ng·mL-1,and(0.48±0.11)h and(0.49±0.17)h,respectively.The Cmax,AUC0-t,AUC0-∞ and Tmax of test and reference preparations of active metabolite benazepril-atin the fasting group were(270.45±69.07)ng·mL-1 and(271.86±65.90)ng·mL-1,(1 490.10±295.32)h×ng·mL-1 and(1 487.96±285.39)h×ng·mL-1,(1 535.19±289.52)h×ng·mL-1 and(1 532.63±285.26)h×ng·mL-1,and(1.45±0.47)h and(1.41±0.33)h,respec-tively.The Cmax,AUC0-t,AUC0-∞ and Tmax of benazepril test and reference preparations in the postprandial group were(102.05±41.17)ng·mL-1and(112.04±49.39)ng·mL-1,(149.19±32.76)h×ng·mL-1 and(151.70±33.78)h×ng·mL-1,(151.02±33.08)h×ng·mL-1 and(154.03±33.99)h×ng·mL-1,and(1.14±0.65)h and(1.09±0.60)h,respectively.The Cmax,AUC0-t,AUC0-∞ and Tmax of benazeprilat test and reference preparations in the postprandial group were(207.71±50.76)ng·mL-1 and(211.68±66.50)ng·mL-1,(1 366.01±292.24)h×ng·mL-1 and(1 343.78±315.41)h×ng·mL-1,(1 414.95±297.71)h×ng·mL-1 and(1 387.03±314.17)h×ng·mL-1,and(2.46±0.87)h and(2.46±0.85)h,respectively.The 90%confidence intervals of the ratio of geometric means of Cmax,AUC0-t and AUC0-∞ of benazepril and benaze-prilat fell within the 80%-125%range.The Tmax was not significantly different between the two preparations(P＞0.05).Conclusion The test and reference preparations of benazepril hydrochlo-ride tablets are bioequivalent.
基金项目
江西省教育厅科学技术基金资助项目(GJJ190112)
维普
万方数据