达沙替尼片在中国健康受试者的生物等效性研究

Bioequivalence of dasatinib tablets in healthy Chinese volunteers

目的:评价2种达沙替尼片(50 mg)空腹及餐后条件下在中国健康受试者体内的生物等效性及安全性。方法:采用随机、开放、单剂量、两周期双交叉试验设计,52例健康受试者参加空腹试验,24例健康受试者参加餐后试验。受试者随机分为2组,分别空腹/餐后口服达沙替尼片受试制剂和参比制剂各50 mg,采用HPLC-MS-MS法测定血浆达沙替尼浓度,计算药动学参数,进行2种达沙替尼片的人体生物等效性及安全性评价。结果:空腹试验受试制剂和参比制剂的主要药动学参数:Cmax分别为(69.95±31.02)和(64.46±34.85)ng·m L-1;Tmax分别为0.75(0.33,2.5)和0.75(0.33,2.5)h;AUC0-t分别为(179.72±62.18)和(173.86±70.00)ng·h·m L-1;AUC0-∞分别为(181.48±62.21)和(175.69±69.77)ng·h·m L-1;Cmax,AUCt和AUC0-t的几何均值比的90%置信区间分别为96.49%~122.35%,95.99%~115.06%和96.06%~114.52%,均符合生物等效性的等效范围要求(80.00%~125.00%)。餐后试验受试制剂和参比制剂的主要药动学参数:Cmax分别为(47.45±19.00)和(47.17±22.93)ng·m L-1;Tmax分别为1.00(0.50,3.00)和1.67(0.67,3.5)h;AUC0-t分别为(196.52±42.96)和(199.48±46.69)ng·h·m L-1;AUC0-∞分别为(199.99±43.49)和(202.73±47.18)ng·h·m L-1;Cmax,AUC0-t和AUC0-∞的几何均值比的90%置信区间分别为91.22%~118.02%,91.82%~106.79%和91.95%~106.89%,均符合生物等效性的等效范围要求(80.00%~125.00%)。试验过程中,空腹试验共出现50例次不良事件,餐后试验中共出现7例次不良事件,均未发生严重不良事件,均无受试者因不良事件退出研究。结论:2种达沙替尼片在空腹及餐后条件下的人体内生物等效、安全。

Objective:To evaluate the bioequivalence and safety of two kinds of dasatinibtablets(50 mg)in healthy Chinese volunteers under fasting and fed conditions.Methods:A single-dose,randomized,open-label,two-period crossover study was designed.Fifty-two healthy volunteers for fasting test and 24 healthy volunteers for fed test were randomly divided into two groups,and received 50 mg of either test or reference dasatinib tablet,respectively,and the plasma concentration of the drug was assayed by HPLC-MS-MS.Pharmacokinetic parameters were calculated and the bioequivalence and safety of the two preparations were evaluated.Results:The major pharmacokinetic parameters of the test and reference preparations in the fasting test were as follows:Cmax(69.95±31.02)and(64.46±34.85)ng·m L-1,Tmax0.75(0.33,2.5)and 0.75(0.33,2.5)h,AUC0-t(179.72±62.18)and(173.86±70.00)ng·h·m L-1,AUC0-∞(181.48±62.21)and(175.69±69.77)ng·h·m L-1;the90%confidence intervals for the ratios of Cmax,AUC0-tand AUC0-∞were 96.49%~122.35%,95.99%~115.06%and 96.06%~114.52%,respectively,which all met the predetermined criteria for assuming bioequivalence(80.00%~125.00%).The major pharmacokinetic parameters of the test preparation and the reference preparation under fed condition were as follows:Cmax(47.45±19.00)and(47.17±22.93)ng·m L-1,Tmax1.00(0.50,3.00)and 1.67(0.67,3.5)h,AUC0-t(196.52±42.96)and(199.48±46.69)ng·h·m L-1,AUC0-∞(199.99±43.49)and(202.73±47.18)ng·h·m L-1;the 90%confidence intervals for the ratios of Cmax,AUC0-tand AUC0-∞were 91.22%~118.02%,91.82%~106.79%and 91.95%~106.89%,respectively,also,which all met the predetermined criteria for assuming bioequivalence(80.00%~125.00%).During the study period,50 cases and 7 cases of adverse events occurred in the fasting test and under the fed condition,respectively.No serious adverse events occurred.None of the subjects withdrew from the study due to adverse events.Conclusion:The test and reference dasatinib tablets are bioequivalent and safe in healthy volunteers.