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 healthy Chinese volunteers

目的评价中国健康受试者空腹及餐后单次口服磷酸奥司他韦胶囊受试制剂和参比制剂的生物等效性。方法采用单中心、随机、开放、两周期、两序列相互交叉设计,空腹组和餐后组受试者分别为52例和40例,每周期口服受试制剂或参比制剂75 mg,采用液相串联质谱法(HPLC-MS/MS)测定血浆中奥司他韦以及活性代谢物奥司他韦羧酸的浓度,WinNonlin 8.2软件计算药代动力学参数,SAS9.4软件进行统计分析。结果空腹组受试制剂与参比制剂中奥司他韦的主要药代动力学参数:C_(max)分别为(101.24±54.55)和(94.95±35.07)ng·mL^(-1),AUC_(0-t)分别为(158.65±32.99)和(169.76±33.78)h·ng·mL^(-1),AUC_(0-∞)分别为(161.14±33.03)和(172.28±33.82)h·ng·mL^(-1),t_(max)分别为0.50和0.50 h;奥司他韦羧酸的主要药代动力学参数C_(max)分别为(316.15±74.05)和(320.64±64.74)ng·mL^(-1),AUC_(0-t)分别为(3355.02±597.88)和(3462.30±664.83)h·ng·mL^(-1),AUC_(0-∞)分别为(3498.10±603.28)和(3587.93±649.51)h·ng·mL^(-1),t_(max)分别为4.00和4.00 h。餐后组受试制剂与参比制剂中奥司他韦的主要药代动力学参数:C_(max)分别为(49.90±13.20)和(49.71±12.25)ng·mL^(-1),AUC0-t分别为(181.32±32.42)和(189.13±32.84)h·ng·mL^(-1),AUC_(0-∞)分别为(184.76±32.69)和(193.49±33.62)h·ng·mL^(-1),t_(max)分别为3.00和3.00 h;奥司他韦羧酸的主要药代动力学参数C_(max)分别为(243.42±37.76)和(250.67±32.84)ng·mL^(-1),AUC_(0-t)分别为(3175.68±558.77)和(3304.51±647.27)h·ng·mL^(-1),AUC_(0-∞)分别为(3312.18±525.37)和(3411.58±633.59)h·ng·mL^(-1),t_(max)分别为6.00和6.00 h。空腹和餐后条件下口服磷酸奥司他韦胶囊受试制剂和参比制剂75 mg后血浆中原型药物奥司他韦和活性代谢物奥司他韦羧酸的药代动力学参数C_(max)、AUC_(0-t)、AUC_(0-∞)的几何均数比的90%置信区间均在80.00%~125.00%。结论磷酸奥司他韦胶囊的受试制剂和参比制剂在空腹和餐后条件下,均具有生物等效性。

Objective To evaluate the bioequivalence of the test and reference preparations of oseltamivir phosphate capsules administered once orally under fasting and fed conditions in Chinese healthy volunteers.Methods The study was designed as single-center,randomized,open,self-crossover.Subjects were assigned to receive a single oral of the test or reference formulation per period at a dose of 75 mg in fasting and fed conditions respectively.The plasma concentration of oseltamivir and its active metabolite oseltamivir carboxylic acid were analyzed by liquid chromatography-mass spectrometry/mass spectrometry(LC-MS/MS).The major pharmacokinetic parameters were calculated by WinNonlin8.2,then the bioequivalence was evaluated by SAS9.4.Results The main pharmacokinetic parameters of oseltamivir under fasting condition for test and reference preparation were as follows:C_(max)were(101.24±54.55)and(94.95±35.07)ng·mL^(-1),AUC_(0-t)were(158.65±32.99)and(169.76±33.78)h·ng·mL^(-1),AUC_(0-∞)were(161.14±33.03)and(172.28±33.82)h·ng·mL^(-1),tmaxwere0.50 and 0.50 h.The main pharmacokinetic parameters of oseltamivir carboxylic acid under fasting condition for test and reference preparation were as follows:Cmaxwere(316.15±74.05)and(320.64±64.74)ng·mL^(-1),AUC_(0-t) were(3355.02±597.88)and(3462.30±664.83)h·ng·mL^(-1),AUC_(0-∞)were(3498.10±603.28)and(3587.93±649.51)h·ng·mL^(-1),tmaxwere 4.00 and 4.00 h.The main pharmacokinetic parameters of oseltamivir under fed condition for test and reference preparation were as follows:Cmaxwere(49.90±13.20)and(49.71±12.25)ng·mL^(-1),AUC0-twere(181.32±32.42)and(189.13±32.84)h·ng·mL^(-1),AUC_(0-∞)were(184.76±32.69)and(193.49±33.62)h·ng·mL^(-1),tmaxwere 3.00 and 3.00 h.The main pharmacokinetic parameters of oseltamivir carboxylic acid under fed condition for test and reference preparation were as follows:Cmax were(243.42±37.76)and(250.67±32.84)ng·mL^(-1),AUC0-twere(3175.68±558.77)and(3304.51±647.27)h·ng·mL^(-1),AUC_(0-∞)were(3312.18±525.37)and(3411.58±633.59)h·ng·mL^(-1),tmaxwere 6.00 and 6.00 h.The 90% confidence intervals of the geometric mean ratios of the main pharmacokinetic parameters Cmax,AUC_(0-t),AUC_(0-∞)of oseltamivir and its active metabolite oseltamivir carboxylic acid of the two preparations under fasting/fed conditions were all within 80%-125%.Conclusion The test and reference preparation of oseltamivir phosphate capsules are bioequivalent under fasting and fed conditions.