磷酸奥司他韦胶囊在中国健康受试者的生物等效性研究

Bioequivalence of Oseltamivir Phosphate Capsules in Chinese Healthy Volunteers

目的评价国产磷酸奥司他韦胶囊与原研胶囊(商品名:Tamiflu)在中国健康人体中的生物等效性与安全性。方法采用单中心、随机、开放、两制剂、两周期、双交叉的试验设计。空腹组和餐后组分别入组54例和64例健康受试者,每周期受试者单次空腹或餐后口服受试药物或参比药物磷酸奥司他韦胶囊75 mg,采用HPLC-MS/MS法测定给药后不同时间点受试者血浆中奥司他韦与奥司他韦羧酸的浓度。采用非房室模型计算药代动力学参数,评价两种药物的生物等效性。结果单次空腹给药受试药物与参比药物血浆奥司他韦药代动力学参数C_(max)分别为(87.33±40.33)和(94.15±50.98)ng·mL^(-1),AUC_(0-t)分别为(161.58±36.92)和(168.32±36.51)ng·h·mL^(-1),AUC_(0-∞)分别为(164.08±37.09)和(170.89±36.53)ng·h·mL^(-1);奥司他韦羧酸药代动力学参数C_(max)分别为(316.74±79.88)和(327.94±83.94)ng·mL^(-1),AUC_(0-t)分别为(3611.87±734.68)和(3714.19±797.94)ng·h·mL^(-1),AUC_(0-∞)分别为(3755.98±692.21)和(3876.03±751.86)ng·h·mL^(-1)。单次餐后给药受试药物与参比药物血浆奥司他韦药代动力学参数Cmax分别为(50.63±13.26)和(54.95±20.51)ng·mL^(-1),AUC_(0-t)分别为(188.34±33.92)和(195.40±37.33)ng·h·mL^(-1),AUC_(0-∞)分别为(192.19±34.29)和(199.82±37.49)ng·h·mL^(-1);奥司他韦羧酸药代动力学参数C_(max)分别为(250.20±39.94)和(262.59±44.48)ng·mL^(-1),AUC_(0-t)分别为(3417.90±598.45)和(3633.24±683.33)ng·h·mL^(-1),AUC_(0-∞)分别为(3549.76±570.94)和(3762.34±654.16)ng·h·mL^(-1)。经对数转换后餐后及空腹C_(max)、AUC_(0-t)和AUC_(0-∞)的几何均数的比值90%CI均落在80.00%~125.00%。本试验中无严重不良事件发生,结果为消失、缓解或稳定。受试药物与参比药物的不良事件发生情况和发生率总体相似。结论磷酸奥司他韦胶囊受试制剂与参比制剂在中国健康受试者空腹和餐后状态下具有生物等效性,安全性良好。

OBJECTIVE To evaluate the bioequivalence and safety between domestic and original oseltamivir capsules in Chinese healthy volunteers.METHODS A single-center,randomized,open,two-preparation,two-sequence,two-period,double-crossover design was used.Fifty-four and sixty-four healthy subjects were respectively enrolled in fasted and fed groups.Domestic oseltamivir capsules was set as test drug and original oseltamivir capsules was set as reference drug oseltamivir capsules,75 mg of them were given on fasting or fed separately.HPLC-MS/MS was used to determine the concentrations of oseltamivir and oseltamivir carboxylate in the plasma at different time points after administration.The non-compartmental model was used to calculate the pharmacokinetic parameters and evaluate the bioequivalence.RESULTS After oral administration of oseltamivir capsules in fasting state,the oseltamivir pharmacokinetic parameters of the test and reference were as follows:C_(max)were(87.33±40.33)and(94.15±50.98)ng·mL^(-1),AUC_(0-t)were(161.58±36.92)and(168.32±36.51)ng·h·mL^(-1),AUC_(0-∞)were(164.08±37.09)and(170.89±36.53)ng·h·mL^(-1),respectively.The oseltamivir carboxylate pharmacokinetic parameters of the test and reference were as follows:C_(max)were(316.74±79.88)and(327.94±83.94)ng·mL^(-1),AUC_(0-t)were(3611.87±734.68)and(3714.19±797.94)ng·h·mL^(-1),AUC_(0-∞)were(3755.98±692.21)and(3876.03±751.86)ng·h·mL^(-1).In fed state,the oseltamivir pharmacokinetic parameters of the test and reference were as follows:C_(max)were(50.63±13.26)and(54.95±20.51)ng·mL^(-1),AUC_(0-t)were(188.34±33.92)and(195.40±37.33)ng·h·mL^(-1),AUC_(0-∞)were(192.19±34.29)and(199.82±37.49)ng·h·mL^(-1).The oseltamivir carboxylate pharmacokinetic parameters of the test and reference were as follows:C_(max)were(250.20±39.94)and(262.59±44.48)ng·mL^(-1),AUC_(0-t)were(3417.90±598.45)and(3633.24±683.33)ng·h·mL^(-1),AUC_(0-∞)were(3549.76±570.94)and(3762.34±654.16)ng·h·mL^(-1).The 90%confidence interval corresponding to the ratio of C_(max),AUC_(0-t)and AUC_(0-∞)of oseltamivir and oseltamivir carboxylate after logarithmic conversion between the test preparation and the reference preparation fell within the range from 80.00%to 125.00%,which met the requirement of bioequivalence.During the whole trial,there were no serious and adverse events occurred,and the results were disappeared,relieved or stable.The incidence of adverse events for the test and reference were generally similar.CONCLUSION The test and reference preparation of oseltamivir capsules are bioequivalent and safe in Chinese healthy subjects.