有限采样法估算盐酸二甲双胍的生物等效性研究  

Study on Bioequivalence Assessment of Metformin Hydrochloride by Limited Sampling Strategy

作　　者：陈丽芳[1,2] 焦建杰[1] 张才丽[1] 娄建石[1] 刘昌孝[3] 

机构地区：[1]天津医科大学基础医学院药理教研室,天津300070 [2]天津市海河医院药剂科,天津300350 [3]天津市药物研究院药动学和药效学国家重点实验室,天津300193

出　　处：《中国药学杂志》2011年第11期860-865,共6页Chinese Pharmaceutical Journal

基　　金：国家973计划资助项目(2004CB518902)

摘　　要：目的本试验以曲线下面积和峰值浓度为评价依据,采用有限采样法估算盐酸二甲双胍的生物等效性,为临床应用提供试验依据。方法试验以20名健康志愿者作为研究对象,口服盐酸二甲双胍参比制剂和受试制剂1 000 mg后采集若干时间点血浆样品,采用高效液相色谱法测定各采样时间点盐酸二甲双胍的血药浓度,用经典方法计算药动学参数,评价生物等效性。另以参比制剂血药浓度数据作为建模数据,采用有限采样法估算药动学参数ρmax、AUC0-24。外部验证以受试制剂数据进行,选择最佳模型进行生物等效性评价。内外部验证均采用Jackknife法。结果结果表明,以2个和3个血药浓度数据点预测的药动学参数回归模型的线性关系较好(r2>0.94),内部和外部验证表明,以血药浓度数据点ρ1,ρ1.5,ρ2,ρ4,ρ10同时估算ρmax、AUC0-24的准确性最好,各参数间比较差异无统计学意义(P<0.05),生物利用度(F)为(100.42±15.05)%。与经典法评价结果一致。结论用有限采样法估算口服盐酸二甲双胍制剂药动学参数是可行的,可以为生物等效性研究提供新的计算方法。OBJECTIVE To develop a limited sampling strategy （LSS） for estimating Pmax and AUC0-24 of metformin hydroehloride preparations to assess the bioequivalence. METHODS Twenty male healthy subjects were enrolled in this bioequivalence study. All subjects were randomly divided into 2 groups and orally administered reference and test formulation of 1 000 mg metformin hydroehloride. The blood concentrations of metformin hydrochloride were determined by a validated HPLC method. A multiple linear regression analysis was developed for estimating AUC0-24 and ρmax. The mefformin hydrochloride concentrations of the reference formulation were used to develop LSS models. The LSS models were internally validated by Jackknife method. The models were also externally validated by bioequivalence assessment of the test metformin hydroehloride formulation based on LSS derived Pmax and AUC0-24 values. The results were compared with those obtained using traditional method. RESULTS Several models for parameter estimation met the predefined criteria （r2 〉0. 94）. Validation tests indicated that the most informative sampling points ρ1, ρ1.5, ρ2, ρ4, ρ10 provided accurate estimations of AUC0-24 and Pmax All parameters had no significant difference （ P 〈 0.05 ）. The bioavailability was （ 100.42 ±15. 05 ） %. It was in concordance with classical assessment. CONCLUSION LSS models provides correct assessment of bioequivalenee between the two mefformin hydrochloride preparations. The method is accurate and desirable for metformin hydrochloride bioequivalence study.

关 键 词：盐酸二甲双胍 经典法 有限采样法 生物等效性 药动学 

分 类 号：R945[医药卫生—微生物与生化药学]