米氮平生物等效性预试验餐前不等效、餐后等效的析因分析

Factorial analysis of premeal and postmeal equivalence of mirtazapine bioequivalence test

目的 评价两种米氮平片在中国健康受试者的生物等效性和安全性。方法 用液相色谱串联质谱(LC-MS/MS)法测定空腹及餐后条件下口服米氮平片后受试者血浆中药物浓度,计算两种条件下药物代谢动力学参数,并进行生物等效性评价。结果 用非房室模型计算药代动力学参数,空腹组米氮平受试制剂/参比制剂血浆中C_(max)、AUC_(0-t)、AUC_(0-∞)主要药代动力学参数几何均数比分别为127.85%、113.03%、113.18%,其90%置信区间(90%CI)分别为108.42%~150.75%、105.96%~120.57%、106.03%~120.81%,C_(max)的90%CI没有完全落在80.00%~125.00%而不等效;餐后组米氮平受试制剂/参比制剂血浆中C_(max)、AUC_(0-t)、AUC_(0-∞)主要药代动力学参数几何均数比分别为95.48%、99.71%、99.74%,其90%CI分别为83.01%~109.84%、92.65%~107.31%、92.36%~107.70%;90%CI均完全落在80.00%~125.00%。结论 受试制剂米氮平片具有餐后生物等效,空腹不等效特点,需要从药物制剂、药物代谢动力学和加强受试者管理等方面析因优化,实现与参比制剂的等效性。

Objective To evaluate the bioequivalence and safety of two Mirtazapine Tablets in healthy Chinese subjects.Methods Plasma concentrations of Mirtazapine Tablets were measured by liquid chromatography-tandem mass spectrometry(LC-MS/MS).The pharmacokinetic parameters were calculated and bioequivalence was evaluated under the two conditions.Results Non-atrioventricular model was used to calculate the pharmacokinetic parameters.The geometric mean ratios of C_(max),AUC_(0-t),and AUC_(0-∞)in plasma of mirtazapine test preparation/reference preparation in fasting group were 127.85%,113.03%,and 113.18%,respectively.The 90%confidence intervals(90%CI)were 108.42%-150.75%,105.96%-120.57%,106.03%-120.81%,respectively,and the C_(max) 90%CI did not completely fall within 80.00%-125.00%and was not equivalent.The geometric mean ratios of the main pharmacokinetic parameters of plasma C_(max),AUC_(0-t),and AUC_(0-∞)of the test preparation/reference preparation of mirtazapine in postprandial group were 95.48%,99.71%,and 99.74%,respectively.The 90%CI was 83.01%-109.84%,92.65%-107.31%,92.36%-107.70%,respectively.90%CI completely fell within 80.00%-125.00%.Conclusion The tested preparation Mirtazapine Tablets have the characteristics of postprandial bioequivalence and fasting non-equivalence,so it is necessary to optimize the factors of drug preparation,pharmacokinetics and strengthening subject management to achieve the equivalence with the reference preparation.