利伐沙班片在中国健康志愿者中的生物等效性研究

Bioequivalence of rivaroxaban tablets in healthy Chinese Volunteers

目的 评价利伐沙班片在中国健康受试者的生物等效性。方法 采用随机、开放、两制剂、空腹及餐后、单次给药、两序列、四周期、完全重复、交叉设计。空腹及餐后试验各入组26例健康受试者,随机分为2组,每周期单次空腹或餐后口服受试制剂或参比制剂10 mg。采用HPLC-MS/MS法测定给药后不同时间点利伐沙班的血药浓度。采用Phoenix Win Nonlin 7. 0软件按非房室模型计算药代动力学参数,并进行生物等效性评价。结果 受试者单次空腹口服利伐沙班受试制剂和参比制剂10 mg后的药动学参数如下:Cmax分别为(159. 25±54. 53),(162. 77±53. 67) ng·m L-1;AUC0-t分别为(1106. 21±431. 51) L和(1086. 22±352. 39) ng·m L-1·h;AUC0-∞分别为(1151. 69±474. 54)和(1115. 49±355. 52) ng·m L-1·h。2种制剂的Cmax、AUC0-t、AUC0-∞的几何均数的比值相对应的90%置信区间分别为89. 57%~106. 49%,92. 79%~108. 02%,93. 58%~108. 93%。2种制剂的Cmax、AUC0-t、AUC0-∞个体内标准方差比值的90%置信区间分别为0. 33~0. 67,0. 59~1. 18,0. 59~1. 20。受试者单次餐后口服利伐沙班受试制剂和参比制剂10 mg后的药动学参数Cmax分别为(242. 19±51. 44)和(233. 57±52. 67) ng·m L-1;AUC0-t分别为(1622. 31±410. 89)和(1652. 71±463. 39) ng·m L-1·h;AUC0-∞分别为(1643. 18±412. 11)和(1667. 15±463. 04) ng·m L-1·h。2种制剂的Cmax、AUC0-t、AUC0-∞几何均数的比值相对应的90%置信区间分别为99. 55%~108. 11%,94. 29%~103. 50%,94. 72%~103. 83%。2种制剂的Cmax、AUC0-t、AUC0-∞个体内标准方差比值的90%置信区间分别为0. 79~1. 71,0. 67~1. 46,0. 66~1. 44。结论 2种利伐沙班片在中国健康受试者体内具有生物等效性。

Objective To evaluate the bioequivalence of the two rivaroxaban tablets in Chinese healthy volunteers.Methods A singledose,randomized,open-label,two-sequence,four-period,fully repetitive,crossover study was conducted in healthy subjects.26 participants were administered test and reference rivaroxaban tablets(10 mg)under fasting and fed condition respectively.The concentrations of rivaroxaban in plasma were determined by HPLC-MS/MS.The pharmacokinetic parameters were calculated and the bioequivalence was compared by non-compartment model of Phoenix WinNonlin 7.0 program.Results The pharmacokinetic parameters for test and reference preparations in fasting state were as follows:Cmax were(159.25±54.53)and(162.77±53.67)ng.mL-1;AUC0-t were(1106.21±431.51)and(1086.22±352.39)ng.mL-1.h;AUC0-∞were(1151.69±474.54)and(1115.49±355.52)ng·mL-1·h;The 90%confidential interval(CI)of Cmax,AUC0-t and AUC0-∞were 89.57%-106.49%,92.79%-108.02%and 93.58%-108.93%;The 90%confidence interval for the test-to-reference ratio of the within-subject variability of Cmax,AUC0-t and AUC0-∞were0.330.67,0.59-1.18 and 0.59-1.20.The pharmacokinetic parameters for test and reference preparations in fed state were as follows:Cmax were(242.19±51.44)and(233.57±52.67)ng·mL-1ng/mL;AUC0-t were(1622.31±410.89)and(1652.71±463.39)ng·mL-1·h;AUC0-∞were(1643.18±412.11)and(1667.15±463.04)ng·mL-1·h;The 90%CI of Cmax,AUC0-t and AUC0-∞were 99.55%-108.11%,94.29%-103.50%and 94.72%-103.83%;The 90%confidence interval for the test-to-reference ratio of the within-subject variability of Cmax AUC0-t and AUC0-∞were 0.79-1.71,0.67-1.46 and 0.66-1.44.Conclusion The test and reference preparations of rivaroxaban were bioequivalent in healthy Chinese subjects.