氢溴酸右美沙芬片在中国健康受试者的生物等效性研究

Bioequivalence of dextromethorphan hydrobromide tablets in healthy Chinese volunteers

目的评价中国健康受试者空腹及餐后单次口服氢溴酸右美沙芬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、两周期交叉设计,空腹组和餐后组受试者各36例,每周期口服受试制剂或参比制剂15 mg,用LC-MS/MS法测定右美沙芬及活性代谢产物O-去甲基右美沙芬的血药浓度,WinNonlin 7.0软件计算药代动力学参数,SAS 9.4软件进行统计分析。结果空腹组受试制剂与参比制剂中右美沙芬的药代动力学参数:C_(max)分别为(2.63±2.55)和(2.55±2.43)ng·mL^(-1),AUC_(0-t)分别为(25.24±29.32)和(25.42±28.51)h·ng·mL^(-1),AUC_(0-∞)分别为(26.13±30.40)和(26.34±29.60)h·ng·mL^(-1),T_(max)分别为2.17和2.31 h,t_(1/2)分别为(7.71±1.94)和(8.00±1.78)h。空腹组受试制剂与参比制剂中O-去甲基右美沙芬的药代动力学参数:C_(max)分别为(2.81±1.36)和(2.60±1.37)ng·mL^(-1),AUC_(0-t)分别为(14.97±6.26)和(14.61±6.10)h·ng·mL^(-1),AUC_(0-∞)分别为(15.51±5.93)和(14.97±6.01)h·ng·mL^(-1),T_(max)分别为1.89和1.82 h,t_(1/2)分别为(9.16±22.07)和(7.44±10.44)h。餐后组受试制剂与参比制剂中右美沙芬的药代动力学参数:C_(max)分别为(4.19±3.28)和(3.77±2.75)ng·mL^(-1),AUC_(0-t)分别为(39.65±43.04)和(38.69±39.44)h·ng·mL^(-1),AUC_(0-∞)分别为(41.84±48.30)和(40.69±43.16)h·ng·mL^(-1),T_(max)分别为2.00和2.25 h,t_(1/2)分别为(8.32±2.35)和(8.31±1.99)h。餐后组受试制剂与参比制剂中O-去甲基右美沙芬的药代动力学参数:C_(max)分别为(3.78±1.67)和(3.21±1.47)ng·mL^(-1),AUC_(0-t)分别为(18.63±5.17)和(18.28±5.60)h·ng·mL^(-1),AUC_(0-∞)分别为(19.00±5.28)和(18.80±5.80)h·ng·mL^(-1),T_(max)分别为2.00和2.00 h,t_(1/2)分别为(5.45±2.57)和(5.72±2.95)h。空腹/餐后条件下口服氢溴酸右美沙芬片受试制剂和参比制剂15 mg后血浆中原型药物右美沙芬的主要药代动力学参数C_(max)、AUC_(0-t)、AUC_(0-∞)的几何均数比的90%置信区间均80.00%~125.00%。结论氢溴酸右美沙芬片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 dextromethorphan hydrobromide tablets 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 10 mg in fasting and fed conditions respectively.The plasma concentration of dextromethorphan and its active metabolite dextrorphan were analyzed by LC-MS/MS.The major pharmacokinetic parameters were calculated by WinNonlin 7.0,then the bioequivalence was evaluated by SAS 9.4.Results The main pharmacokinetic parameters of a single oral dextromethorphan hydrobromid under fasting condition for test and reference preparation were as follows:C_(max)(2.63±2.55)and(2.55±2.43)ng·mL^(-1),AUC_(0-t)(25.24±29.32)and(25.42±28.51)h·ng·mL^(-1),AUC_(0-∞)(26.13±30.40)and(26.34±29.60)h·ng·mL^(-1),T_(max)2.17 and 2.31 h,t_(1/2)(7.71±1.94)and(8.00±1.78)h.The main pharmacokinetic parameters of a single oral dextrorphan under fasting condition for test and reference preparation were as follows:C_(max)(2.81±1.36)and(2.60±1.37)ng·mL^(-1),AUC_(0-t)(14.97±6.26)and(14.61±6.10)h·ng·mL^(-1),AUC_(0-∞)(15.51±5.93)and(14.97±6.01)h·ng·mL^(-1),T_(max)1.89 and 1.82 h,t_(1/2)(9.16±22.07)and(7.44±10.44)h.The main pharmacokinetic parameters of a single oral dextromethorphan hydrobromid under fed condition for test and reference preparation were as follows:C_(max)(4.19±3.28)and(3.77±2.75)ng·mL^(-1),AUC_(0-t)(39.65±43.04)and(38.69±39.44)h·ng·mL^(-1),AUC_(0-∞)(41.84±48.30)and(40.69±43.16)h·ng·mL^(-1),T_(max)2.00 and 2.25 h,t_(1/2)(8.32±2.35)and(8.31±1.99)h.The main pharmacokinetic parameters of a single oral dextrorphan under fed condition for test and reference preparation were as follows:C_(max)(3.78±1.67)and(3.21±1.47)ng·mL^(-1),AUC_(0-t)(18.63±5.17)and(18.28±5.60)h·ng·mL^(-1),AUC_(0-∞)(19.00±5.28)and(18.80±5.80)h·ng·mL^(-1),T_(max)2.00 and 2.00 h,t_(1/2)(5.45±2.57)and(5.72±2.95)h.The 90%confidence intervals of the geometric mean ratios of the main pharmacokinetic parametersC_(max),AUC_(0-t),AUC_(0-∞)of dextromethorphan and its active metabolite dextrorphan of the two preparations under fasting/feding conditions were all within 80%-125%.Conclusion The test and reference preparation of dextromethorphan hydrobromid tablets are bioequivalent under fasting and fed conditions.