LC-MS/MS法测定人血浆中曲格列汀的浓度及2种片剂药动学比较研究

Determination of trelagliptin in human plasma by LC-MS/MS and comparison of pharmacokinetics of two kinds of trelagliptin succinate tablets

目的建立测定人血浆中曲格列汀浓度的LC-MS/MS法,考察空腹和餐后条件下2种琥珀酸曲格列汀片的人体药动学特征,并初步评价其生物等效性。方法空腹8例健康受试者和餐后8例健康受试者,采用单中心、单剂量、随机、开放、双周期、双交叉试验设计,受试者单次口服琥珀酸曲格列汀片受试制剂100 mg和参比制剂(Zafatekl■)100 mg,清洗期18 d,用LC-MS/MS法测定血浆中曲格列汀的浓度,用WinNonlin7.0软件按非房室模型计算药动学参数,评价受试药物和参比药物的生物等效性。结果空腹试验受试制剂和参比制剂主要药动学参数:Tmax分别为(2.31±1.0)、(1.34±0.94)h;Cmax分别为(0.6±0.2)、(0.56±0.1)mg/L;AUC0-t分别为(6.25±1.16)、(6.14±1.08)(mg·h)/L;AUC0-∞分别为(6.34±1.17)、(6.22±1.09)(mg·h)/L。餐后试验受试制剂和参比制剂主要药动学参数:Tmax分别为(1.69±0.73)、(2.19±1.3)h;Cmax分别为(0.58±0.18)、(0.56±0.18)mg/L;AUC0-t分别为(6.28±0.97)、(6.45±0.95)(mg·h)/L;AUC0-∞分别为(6.37±0.96)、(6.56±0.94)(mg·h)/L。空腹试验受试制剂和参比制剂Cmax、AUC0-t、AUC0-∞的几何均值比90%置信区间分别为83.64%~129.13%、95.18%~108.54%和95.23%~108.84%。餐后试验受试制剂和参比制剂Cmax、AUC0-t、AUC0-∞的几何均值比90%置信区间分别为82.41%~131.22%、92.85%~101.92%和92.54%~101.71%。结论所建立的LC-MS/MS法能快速、准确测定人血浆中曲格列汀的浓度;两制剂在本试验空腹及餐后给药条件下Cmax不具有生物等效性。

Objective To establish a liquid chromatography-tandem mass spectrometry(LC-MS/MS)method for the determination of trelagliptin in human plasma.The pharmacokinetics and the bioequivalence of trelagliptin succinate tablets were preliminary studied under fasting and fed conditions.Methods 8 healthy volunteers and 8 healthy volunteers were recruited respectively in fasting and fed conditions,by using single-center,single-dose,open,randomized,double cycle and self-crossover design test,a single oral dose of trelagliptin succinate tablets was test preparation(T)100 mg and reference preparation(R)100 mg,and the cleaning period was 18 days.Drug concentration in plasma was determined by LC-MS/MS.The pharmacokinetic parameters of trelagliptin were calculated with noncompartmental analysis method by WinNonLin 7.0,and the bioequivalence was assessed.Results The main pharmacokinetic parameters under fasting condition of T and R were as follows:Tmax were(2.31±1.0),(1.34±0.94)h,Cmax were(0.6±0.2),(0.56±0.1)mg/L,AUC0-t were(6.25±1.16),(6.14±1.08)(mg·h)/L,AUC0-∞were(6.34±1.17),(6.22±1.09)(mg·h)/L.The main pharmacokinetic parameters under fed condition of T and R were as follows:Tmax were(1.69±0.73),(2.19±1.3)h,Cmax were(0.58±0.18),(0.56±0.18)mg/L,AUC0-t were(6.28±0.97),(6.45±0.95)(mg·h)/L,AUC0-∞were(6.37±0.96),(6.56±0.94)(mg·h)/L.The 90%CIs for the geometric mean ratios of Cmax,AUC0-t and AUC0-∞of T and R were 83.64%~129.13%,95.18%~108.54%and 95.23%~108.84%,respectively.The 90%CIs for the geometric mean ratios of Cmax,AUC0-t and AUC0-∞of T and R were 82.41%~131.22%,92.85%~101.92%and 92.54%~101.71%,respectively.Conclusion The established LC-MS/MS method is rapid and accurate for the determination of trelagliptin in human plasma.Under the conditions of fasting and fed administration,the Cmax of domestic trelagliptin succinate tablets is no similar to those of imported trelagliptin succinate tablets.