盐酸托莫西汀胶囊在中国健康志愿者中的生物等效性研究

Bioequivalence of atomoxetine hydrochloride capsules in healthy Chinese volunteers

目的:评价盐酸托莫西汀胶囊(25 mg)在中国健康成年志愿者体内的药动学特征及国产受试制剂与参比制剂的生物等效性。方法:空腹与餐后试验各入组24例健康志愿者,采用单剂量随机、开放、两周期交叉试验设计,志愿者两周期分别服用25 mg盐酸托莫西汀受试制剂或参比制剂,清洗期为7 d,采集给药后36 h内的血样,通过高效液相色谱-串联质谱法(HPLC-MS/MS)检测血浆中托莫西汀浓度,非房室模型计算药动学参数,根据C_(max),AUC_(0-t),AUC_(0-∞)几何均值比值(GMR)90%置信区间判断两制剂生物等效性。结果:空腹试验受试制剂与参比制剂托莫西汀主要药动学参数C_(max)分别为(282.13±91.45)和(271.42±79.44)ng·mL^(-1),AUC_(0-t)分别为(2009.91±1258.81)和(1942.78±1198.58)ng·h·mL^(-1),AUC_(0-∞)分别为(2051.51±1306.58)和(1982.65±1242.27)ng·h·mL^(-1)。餐后试验受试制剂与参比制剂托莫西汀的主要药动学参数C_(max)分别为(189.26±77.24)和(185.80±63.09)ng·mL^(-1),AUC_(0-t)分别为(1804.43±1107.08)和(1740.68±1003.93)ng·h·mL^(-1),AUC_(0-∞)分别为(1847.90±1164.11)和(1779.44±1053.44)ng·h·mL^(-1)。空腹与餐后条件下C_(max),AUC_(0-t),AUC_(0-∞)的GMR的90%置信区间均落在80.00%~125.00%等效范围内。试验中无严重不良事件发生。结论:在空腹和餐后状态下,国产受试制剂与参比制剂在中国健康志愿者中具有生物等效性,安全性良好。

Objective:To study the pharmacokinetics of atomoxetine hydrochloride and to evaluate the bioequivalence of domestic generic and reference atomoxetine hydrochloride(25 mg)in healthy Chinese volunteers.Methods:A randomized,open,two-period crossover study with a 7-day washout period was conducted under fasting and fed conditions in healthy Chinese volunteers(24 subjects/condition).Eligible subjects randomly received a 25 mg single dose of either the test or the reference formulation.A serial blood samples were collected over a 36-hour interval following the administration.The concentration of atomoxetine in plasma was determined by validated HPLC-MS/MS method.Noncompartmental model was applied for pharmacokinetic analysis.The geometric mean ratios(GMRs)and the corresponding 90%confidence intervals of C_(max),AUC_(0-t)and AUC_(0-∞)were acquired for bioequivalence analysis.Results:The pharmacokinetic parameters of the test and reference capsules under fasting condition are as follows:C_(max)are(282.13±91.45)and(271.42±79.44)ng·mL^(-1);AUC_(0-t)are(2009.91±1258.81)and(1942.78±1198.58)ng·h·mL^(-1),AUC_(0-∞)are(2051.51±1306.58)and(1982.65±1242.27)ng·h·mL^(-1).The pharmacokinetic parameters of the test and reference capsules under fed condition are as follows:C_(max)are(189.26±77.24)and(185.80±63.09)ng·mL^(-1);AUC_(0-t)are(1804.43±1107.08)and(1740.68±1003.93)ng·h·mL^(-1),AUC_(0-∞)are(1847.90±1164.11)and(1779.44±1053.44)ng·h·mL^(-1).The 90%confidential intervals of the GMRs of C_(max),AUC_(0-t)and AUC_(0-∞)fell within the bioequivalence criteria(80.00%~125.00%).No serious adverse event was observed.Conclusion:The domestic atomoxetine hydrochloride was bioequivalence to the reference formulation.Both formulations were generally well tolerated.