达比加群酯胶囊在中国健康受试者中的生物等效性和药代动力学研究

Bioequivalence and pharmacokinetics of dabigatran etexilate capsules in healthy Chinese subjects

目的研究2种达比加群酯胶囊在中国健康受试者的生物等效性。方法空腹试验入组56例健康受试者,餐后试验入组48例健康受试者,随机、开放、四周期、完全重复交叉单剂量口服达比加群酯胶囊受试制剂或参比制剂150 mg。用液相色谱串联质谱法测定给药后不同时间点达比加群的血药浓度。用非房室模型计算药代动力学参数,评价2种制剂的生物等效性。结果空腹试验受试和参比制剂的总达比加群的主要药代动力学参数:Cmax分别为(194.26±66.45)和(198.21±63.04)ng·mL^(-1),AUC_(0-t)分别为(1503.09±536.02)和(1551.04±557.71)h·ng·mL^(-1),AUC_(0-∞)分别为(1547.73±539.14)和(1597.85±558.33)h·ng·mL^(-1)。餐后试验受试和参比制剂的总达比加群的主要药代动力学参数:Cmax分别为(175.84±50.85)和(172.78±56.21)ng·mL^(-1),AUC_(0-t)分别为(1401.10±419.33)和(1386.06±448.49)h·ng·mL^(-1),AUC_(0-∞)分别为(1443.68±427.61)和(1429.02±456.64)h·ng·mL^(-1)。受试制剂与参比制剂主要药代动力学参数经对数转换后几何均值比值的90%置信区间(CI)均在80.00%~125.00%,且个体内变异比率90%CI上限值均≤2.5。空腹组与餐后组不良事件发生率分别为17.86%和19.15%,均未发生严重不良事件。结论2种达比加群酯胶囊在空腹及餐后状态下均具有生物等效性,且安全性良好。

Objective To study the bioequivalence of two dabigatran etexilate capsules in healthy Chinese subjects.Methods Fifty-six healthy subjects were enrolled in the fasted group and forty-eight healthy subjects were enrolled in the fed group.Randomized,open,four-cycle,complete repeat cross single dose oral dabigatran etexilate capsule test preparation or reference preparation 150 mg.The plasma concentration of dabigatran was determined by liquid chromatography/tandem mass spectrometry at different time points after administration.The non-compartmental model was used to calculate the pharmacokinetic parameters and evaluate the bioequivalence of the two formulations.Results Main pharmacokinetic parameters of the total dabigatran of the test preparation and the reference preparation in the fasted group:C_(max)were(194.26±66.45)and(198.21±63.04)ng·mL^(-1);AUC_(0-t)were(1503.09±536.02)and(1551.04±557.71)h·ng·m L^(-1);AUC0-∞were(1547.73±539.14)and(1597.85±558.33)h·ng·m L^(-1).Main pharmacokinetic parameters of the total dabigatran of the test preparation and the reference preparation in the fed group:C_(max_were(175.84±50.85)and(172.78±56.21)ng·m L^(-1);AUC_(0-t)were(1401.10±419.33)and(1386.06±448.49)h·ng·m L^(-1);AUC_(0-∞)were(1443.68±427.61)and(1429.02±456.64)h·ng·m L^(-1).The 90%confidence interval of geometric mean ratio of major pharmacokinetic parameters of test preparation and reference preparation after logarithmic conversion fell in the range of 80.00%-125.00%,and the 90%confidence interval upper limit of variation ratio within individuals was≤2.5.The incidence of adverse events in fasted group and fed group was17.86%and 19.15%,with no serious adverse events.Conclusion The two dabigatran etexilate capsules were bioequivalent under fasted and fed conditions,and good security.