盐酸帕罗西汀肠溶缓释片在中国健康受试者中的生物等效性研究

Bioequivalence study of paroxetine hydrochloride enteric-coated sustained-release tablets in Chinese healthy volunteers

目的 评价空腹和餐后口服2种盐酸帕罗西汀肠溶缓释片的生物等效性,以及评估两制剂的安全性。方法 空腹和餐后分别采用随机、开放、两制剂、四周期/三周期、双序列/三序列、完全重复/部分重复(仅重复参比制剂)的平均生物等效性试验设计。空腹和餐后分别入组46例和36例健康受试者,随机交叉单次口服盐酸帕罗西汀肠溶缓释片受试制剂和参比制剂25 mg,用LC-MS/MS法测定血浆中帕罗西汀的浓度。使用SAS V9.4软件进行药代动力学分析、生物等效性评价和安全性统计分析。通过参比制剂标度的平均生物等效性(RSABE)的方法来评价两种制剂的生物等效性。结果 空腹组受试制剂和参比制剂帕罗西汀的主要药代动力学参数C_(max)分别为(6.10±5.34)和(5.11±4.91)ng·mL^(-1),AUC_(0-t)分别为(178.46±228.48)和(155.52±228.22)ng·h·mL^(-1),AUC_(0-∞)分别为(193.95±284.85)和(174.57±315.52)ng·h·mL^(-1),t_(1/2)分别为(15.54±5.96)和(15.73±6.66)h。餐后组受试制剂和参比制剂帕罗西汀C_(max)分别为(7.38±7.56)和(6.00±4.93)ng·mL^(-1),AUC_(0-t)分别为(207.73±251.73)和(166.59±173.34)ng·h·mL^(-1),AUC_(0-∞)分别为(219.95±279.84)和(176.75±199.82)ng·h·mL^(-1),t_(1/2)分别为(15.04±4.11)和(14.63±3.94)h。在空腹和餐后条件下,参比制剂帕罗西汀的PK参数C_(max)、AUC_(0-t)和AUC_(0-∞)的个体内变异系数均大于30%,故空腹和餐后均采用RSABE方法进行生物等效性评价。空腹状态下,受试制剂和参比制剂C_(max)、AUC_(0-t)和AUC_(0-∞)的95%置信区间上限值均小于0,几何均值比的点估计值分别为119.32%,122.59%和122.27%。餐后状态下,受试制剂和参比制剂C_(max)、AUC_(0-t)和AUC_(0-∞)的95%置信区间上限值均小于0,几何均值比的点估计值分别为113.05%,119.14%和118.88%。空腹组和餐后组的不良事件发生率分别为37.78%和48.57%,研究过程中无严重不良事件发生。结论 在空腹和餐后状态下,盐酸帕罗西汀肠溶缓释片的受试制剂与参比制剂具有生物等效性,且安全性良好。

Objective To evaluate the bioequivalence of two paroxetine hydrochloride enteric-coated sustained-release tablets and their safety in Chinese healthy volunteers in fasting and fed conditions.Methods A randomized,open-label,two-preparation,four periods/three periods,two-sequence/three-sequence,complete/partially repeated(only reference preparation was repeated)average bioequivalence design was respectively adopted under fasting and fed state.A total of 46 subjects in fasting and 36 subjects in fed state received single oral dose 25 mg of test(T)and reference(R)paroxetine hydrochloride enteric-coated sustained-release tablets,respectively.Plasma concentration of paroxetine was determined by LC-MS/MS method.SAS V9.4 software was used for pharmacokinetic analysis,bioequivalence evaluation and safety analysis.The bioequivalence was evaluated by reference-scaled average bioequivalence(RSABE)method.Results In the fasting condition,the pharmacokinetic parameters of T and R were as follows:C_(max)were(6.10±5.34)and(5.11±4.91)ng·mL^(-1),AUC_(0-t)were(178.46±228.48)and(155.52±228.22)ng·h·mL^(-1),AUC_(0-∞)were(193.95±284.85)and(174.57±315.52)ng·h·mL^(-1),t_(1/2)were(15.54±5.96)and(15.73±6.66)h,respectively.In the fed condition,the pharmacokinetic parameters of T and R were as follows:C_(max)were(7.38±7.56)and(6.00±4.93)ng·mL^(-1),AUC_(0-t)were(207.73±251.73)and(166.59±173.34)ng·h·mL^(-1),AUC_(0-∞)were(219.95±279.84)and(176.75±199.82)ng·h·mL^(-1),t_(1/2) were(15.04±4.11)and(14.63±3.94)h,respectively.Because the within-subject coefficients of variation of C_(max),AUC_(0-t)and AUC_(0-∞)of R were all greater than 30%under both fasting and fed conditions,RSABE method was adopted in both states.In fasting state,the upper bound of 95%confidence interval of C_(max),AUC_(0-t)and AUC_(0-∞)were all less than 0,and the point estimation(Pointest)values of geometric mean ratio(GMR)of T/R were 119.32%,122.59%and 122.27%,respectively.In fed state,the critbound of C_(max),AUC_(0-t)and AUC_(0-∞)were all less than 0,and the pointest values of GMR of T/R were113.05%,119.14%and 118.88%,respectively.The incidence of adverse events in fasting and fed group was37.78%and 48.57%,respectively,and there were no serious adverse events during the study.Conclusion The test and reference preparations of paroxetine hydrochloride enteric-coated sustained-release tablets were bioequivalent and safe under both fasting and fed states.