利伐沙班片在中国健康受试者中的生物等效性研究

Bioequivalence of rivaroxaban tablets in Chinese healthy volunteers

目的评价2种利伐沙班片在中国健康受试者的生物等效性及安全性。方法采用随机、开放、四周期、完全重复交叉试验设计,空腹和餐后各入组36例健康受试者,受试者单剂量口服利伐沙班片受试制剂和参比制剂15mg,用液相色谱串联质谱法(LC-MS/MS)测定健康受试者血浆中利伐沙班药物浓度,用WinNonlin 7.0软件计算药代动力学参数,评价生物等效性。结果受试者空腹单剂量口服受试制剂和参比制剂后血浆中利伐沙班的主要药代动力学参数:Cmax分别为(246.28±78.52),(223.15±72.03)ng·mL^-1,AUC0-t分别为(1578.97±420.08),(1486.26±441.21)ng·h·mL^-1,AUC0-∞分别为(1670.22±412.31),(1568.73±478.14)ng·h·mL^-1。2种制剂的Cmax、AUC0-t、AUC0-∞经对数转换后90%可信区间分别为103.44%~117.44%,101.01%~113.72%,101.56%~114.74%。2种制剂的Cmax、AUC0-t、AUC0-∞个体内标准方差比值的90%置信区间上限值分别为1.30,1.03和1.11。餐后单剂量口服受试制剂和参比制剂后血浆中利伐沙班主要药代动力学参数:Cmax分别为(324.83±52.62),(302.99±46.73)ng·mL^-1,AUC0-t分别为(1997.63±427.77),(1952.35±488.12)ng·h·mL^-1,AUC0-∞分别为(2008.91±427.77),(1964.74±490.76)ng·h·mL-1。2种制剂的Cmax、AUC0-t、AUC0-∞经对数转换后90%可信区间分别为102.61%~112.34%,98.89%~106.93%,98.80%~106.94%。2种制剂的Cmax、AUC0-t、AUC0-∞个体内标准方差比值的90%置信区间上限值分别为1.60,1.44,1.42。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 two kinds of rivaroxaban tablets in Chinese healthy volunteers.Methods The study was designed as a randomized,open-label,four-period complete and replicate crossover.A total of 36 volunteers under fasting condition and 36 volunteers under fed condition were given a single oral dose of 15 mg rivaroxaban tablet of test and reference,respectively.The concentration of rivaroxaban in plasma were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS).The pharmacokinetic parameters were calculated by WinNonlin 7.0 program and the bioequivalence was evaluated.Results The main pharmacokinetic parameters of a single oral dose of rivaroxaban tablets under fasting condition for T and R were as follows:Cmax(246.28±78.52),(223.15±72.03)ng·mL^-1;AUC0-t(1578.97±420.08),(1486.26±441.21)ng·h·mL^-1;AUC0-∞(1670.22±412.31),(1568.73±478.14)ng·h·mL-1.The 90% confidential interval(CI)of Cmax,AUC0-t and AUC0-∞were 103.44%~117.44%,101.01%~113.72%,101.56%~114.74%;The upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject of Cmax,AUC0-t and AUC0-∞were 1.30,1.03,and 1.11.The main pharmacokinetic parameters of a single oral dose of rivaroxaban tablets under fed condition for T and R were as follows:Cmax(324.83±52.62),(302.99±46.73)ng·mL^-1;AUC0-t(1997.63±427.77),(1952.35±488.12)ng·h·mL-1;AUC0-∞(2008.91±427.77),(1964.74±490.76)ng·h·mL^-1.The 90%CI of Cmax,AUC0-t and AUC0-∞ were 102.61%~112.34%,98.89%~106.93%,98.80%~106.94%.The upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject of Cmax,AUC0-t and AUC0-∞ were 1.60,1.44,and 1.42.Conclusion The two preparations of rivaroxaban tablets were bioequivalent in Chinese healthy volunteers.