盐酸贝那普利片及活性代谢物在中国健康受试者中的生物等效性研究

Bioequivalence of Benazepril Hydrochloride Tablet and Its Active Metabolites in Healthy Chinese Subjects

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C max、AUC 0-t、AUC 0-∞进行分析;T max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:C max分别为(207.86±70.77)ng·mL^(-1)和(205.20±70.37)ng·mL^(-1);AUC 0-t分别为(168.91±36.03)h×ng·mL^(-1)和(170.23±38.37)h×ng·mL^(-1);AUC 0-∞分别为(171.01±36.15)h×ng·mL^(-1)和(172.27±38.49)h×ng·mL^(-1);T max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:C max分别为(270.45±69.07)ng·mL^(-1)和(271.86±65.90)ng·mL^(-1);AUC 0-t分别为(1490.10±295.32)h×ng·mL^(-1)和(1487.96±285.39)h×ng·mL^(-1);AUC 0-∞分别为(1535.19±289.52)h×ng·mL^(-1)和(1532.63±285.26)h×ng·mL^(-1);T max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C max分别为(102.05±41.17)ng·mL^(-1)和(112.04±49.39)ng·mL^(-1);AUC 0-t分别为(149.19±32.76)h×ng·mL^(-1)和(151.70±33.78)h×ng·mL^(-1);AUC 0-∞分别为(151.02±33.08)h×ng·mL^(-1)和(154.03±33.99)h×ng·mL^(-1);T max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C max分别为(207.71±50.76)ng·mL^(-1)和(211.68±66.50)ng·mL^(-1);AUC 0-t分别为(1366.01±292.24)h×ng·mL^(-1)和(1343.78±315.41)h×ng·mL^(-1);AUC 0-∞分别为(1414.95±297.71)h×ng·mL^(-1)和(1387.03±314.17)h×ng·mL^(-1);T max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C max、AUC 0-t、AUC 0-∞的几何均值比值的90%置信区间均在80%~125%;T max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。

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.Single-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,AUC 0-t and AUC 0-∞were analyzed using the non-atrioventricular mode of WinNonlin.T max was analyzed by nonparametric rank sum test.Results The C max,AUC 0-t,AUC 0-∞and T max of benazepril test and reference preparations 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 C max,AUC 0-t,AUC 0-∞and T max of test and reference preparations of active metabolite benazeprilatin the fasting group were(270.45±69.07)ng·mL^(-1) and(271.86±65.90)ng·mL^(-1),(1490.10±295.32)h×ng·mL^(-1) and(1487.96±285.39)h×ng·mL^(-1),(1535.19±289.52)h×ng·mL^(-1) and(1532.63±285.26)h×ng·mL^(-1),and(1.45±0.47)h and(1.41±0.33)h,respectively.The C max,AUC 0-t,AUC 0-∞and T max of benazepril test and reference preparations in the postprandial group were(102.05±41.17)ng·mL^(-1) and(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 C max,AUC 0-t,AUC 0-∞and T max 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),(1366.01±292.24)h×ng·mL^(-1) and(1343.78±315.41)h×ng·mL^(-1),(1414.95±297.71)h×ng·mL^(-1) and(1387.03±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 C max,AUC 0-t and AUC 0-∞of benazepril and benazeprilat fell within the 80%-125%range.The T max was not significantly different between the two preparations(P>0.05).Conclusion The test and reference preparations of benazepril hydrochloride tablets are bioequivalent.