达比加群酯胶囊人体生物等效性及安全性评价

Bioequivalence and safety evaluation of dabigatran capsule in human

目的:评价达比加群酯(dabigatran)胶囊在健康受试者空腹、餐后状态下的人体生物等效性及安全性。方法:采取开放、单剂量、随机、重复、四周期设计,分别进行空腹组(60例)及餐后组(40例)试验,采用高效液相色谱-串联质谱法测定受试者每周期口服达比加群酯胶囊受试制剂或参比制剂(泰毕全)后15个不同时间的达比加群酯浓度。采用置信区间法(confidence interval,CI)进行生物等效性评价,且需要满足受试制剂与参比制剂的个体内标准方差比率(σWT/σWR)的90%CI上限≤2.5。试验全程对受试者不良事件(adverse event,AE)进行监测。结果:空腹试验共60例受试者完成试验,餐后试验共37例受试者完成试验。空腹试验受试者平均年龄(38.8±7.11)岁,男女比例为1∶1.86,游离达比加群的药动学参数(Cmax,AUC0~t,AUC0~inf)的几何均值比值90%CI分别为98.07%~111.06%,97.74%~111.60%及97.96%~110.77%,总体达比加群的药动学参数(Cmax,AUC0~t,AUC0~inf)的几何均值比值90%CI分别为97.15%~110.24%,96.65%~111.06%和97.34%~110.34%。餐后试验受试者平均年龄(40.7±6.74)岁,男女比例为0.67∶1,游离达比加群的药动学参数(Cmax,AUC0~t,AUC0~inf)的几何均值比值90%CI分别为86.47%~98.98%,93.18%~101.49%及94.49%~102.29%,总体达比加群的药动学参数(Cmax,AUC0~t,AUC0~inf)的几何均值比值90%CI分别为86.42%~99.12%,94.36%~102.25%和94.75%~102.32%。试验中共发生22例次与试验相关AE。结论:两种达比加群酯胶囊制剂生物等效,健康人体中应用安全性良好。

Objective: To evaluate the bioequivalence and safety of dabigatran capsule in healthy subjects on fasting and postprandial state.Methods: An open,single-dose,randomized,repeated,four-period-clinical trial was designed and adopted.60 healthy subjects were involved in fasting test and 40 healthy subjects in fed test.Drug concentrations at 15 different time points after oral administration of dabigatran capsules were determined by High-performance liquid chromatography-tandem mass spectrometry(MS).Applicants used the average bioequivalence approach with BE limits of 80% ~ 125%.The within-subject variability of the test and reference products was compared and the upper limit of 90% confidence interval for the test-to-reference ratio of the within-subject variability should be≤2.5.Adverse events(AE) were monitored during the whole test.Results: A total of 60 subjects completed the fasting trial and 37 subjects completed the postprandial trial.The mean age of subjects in the fasting trial was38.8 ± 7.11 years,the ratio of males to females was 1∶ 1.86,the 90% confidence intervals of the geometric mean ratio of Cmax,AUC0-t and AUC0-INFwere 98.07% ~ 111.06%,97.74% ~ 111.60% and 97.96 ~ 110.77%,respectively,and the 90% confidence intervals of the geometric mean ratio of Cmax,AUC0-t and AUC0-INFwere97.15% ~ 110.24%,96.65% ~ 111.06% and 97.34% ~ 110.34%,respectively.The average age of the subjects in the postprandial trial was 40.7 ± 6.74 years,the male to female ratio was 0.67∶ 1,the 90% confidence intervals for the geometric mean ratio of Cmax,AUC0-t and AUC0-INF were 86.47% ~ 98.98%,93.18% ~ 101.49%and 94.49% ~ 102.29%,respectively,and the 90% confidence intervals of the geometric mean ratio of Cmax,AUC0-t and AUC0-INF were 86.42% ~ 99.12%,94.36% ~ 102.25% and 94.75% ~ 102.32%,respectively.There were 22 cases of AE associated with the test.Conclusion: Two formuations of dabigatran capsules are bioequivalent and safe in healthy human.