甲硝唑片在中国健康受试者中的生物等效性研究

Bioequivalence test of metronidazole tablets in healthy human in China

目的评价甲硝唑片受试和参比试剂在中国健康受试者中的生物等效性。方法采用单剂量、两周期、随机、开放、自身交叉、空腹和餐后两种状态下的试验设计。空腹和餐后试验分别入组24例受试者,每周期分别单次口服甲硝唑片受试和参比制剂200 mg。用高效液相色谱串联质谱(HPLC-MS/MS)法测定血样中甲硝唑的药物浓度,应用非房室模型计算药代动力学参数并用SAS 9.3软件进行生物等效性分析。结果空腹试验口服甲硝唑片受试制剂和参比制剂的主要药动学参数:C_(max)分别为(4855.00±1383.97)和(4799.13±1195.32)ng·mL^(-1),AUC_(0-t)分别为(54834.68±12697.88)和(55931.35±11935.28)ng·h·mL^(-1),AUC_(0-∞)分别为(56778.09±13937.76)和(57922.83±13260.54)ng·h·mL^(-1),T_(max)分别为1.17和1.00 h,t_(1/2)别为(8.99±1.76)和(9.11±1.73)h。C_(max)、AUC_(0-t)和AUC_(0-∞)几何平均值(90%置信区间,CI)均在等效区间80.00%~125.00%。餐后试验口服甲硝唑片受试制剂和参比制剂主要药代动力学参数:C_(max)分别为(4057.08±655.08)和(4044.17±773.98)ng·mL^(-1),AUC_(0-t)分别为(55956.42±12228.12)和(55121.04±11784.55)ng·h·mL^(-1),AUC_(0-∞)分别为(58212.83±13820.00)和(57350.38±13229.46)ng·h·mL^(-1),T_(max)分别为2.50和2.25 h,t_(1/2)别为(9.37±1.68)和(9.37±1.79)h。C_(max)、AUC_(0-t)和AUC_(0-∞)几何均值(90%置信区间CI)均在等效区间80.00%~125.00%。结论甲硝唑片受试制剂和参比制剂对于中国健康成年受试者在空腹和餐后条件下均具有生物等效性。

Objective To evaluate the bioequivalence of metronidazole tablet and reference formulation in Chinese healthy subjects.Methods A single-dose,two-cycle,randomized,open,self-crossover trial was designed with 48 healthy subjects randomly assigned to fasting or postprandial group.For each group,a single oral dose of metronidazole tablet(200 mg)or a reference preparation(200 mg)per cycle were enrolled.The concentration of metronidazole in plasma was measured by high performance liquid chromatography tandem mass spectrometry(HPLC-MS/MS).The non-compartmental model was applied to calculate the pharmacokinetic parameters for bioequivalence analysis via SAS 9.3 software.Results The main pharmacokinetic parameters of test and reference metronidazole tablets in the fasting group were as follows,the C_(max)were(4855.00±1383.97)and(4799.13±1195.32)ng·h·mL^(-1);the AUC_(0-t)were(54834.68±12697.88)and(55931.35±11935.28)ng·h·mL^(-1);the AUC_(0-∞)were(56778.09±13937.76)and(57922.83±13260.54)ng·h·mL^(-1);the T_(max)were respectively 1.17 and 1.00 h;t_(1/2)were(8.99±1.76)and(9.11±1.73)h,respectively.The ratio of the geometric mean and its 90%confidence intervals(CI)of C_(max),AUC_(0-t)and AUC_(0-∞)were all within the equivalent interval of 80.00%-125.00%.As for postprandial conditions,the main pharmacokinetic parameters of test and reference metronidazole tablets were as follows,the C_(max)were(4057.08±655.08)and(4044.17±773.98)ng·h·mL^(-1);the AUC_(0-t)were(55956.42±12228.12)and(55121.04±11784.55)ng·h·mL^(-1);the AUC_(0-∞)were(58212.83±13820.00)and(57350.38±13229.46)ng·h·mL^(-1);the T_(max)were 2.50 and 2.25 h;the t_(1/2)were(9.37±1.68)and(9.37±1.79)h,respectively.The ratio of the geometric mean and 90%CI of C_(max),AUC_(0-t)and AUC_(0-∞)were all within the equivalent interval of 80.00%-125.00%.Conclusion The two preparations were bioequivalent to Chinese healthy adult volunteers under both fasting and fed conditions.