LSS法估算中国健康志愿者口服阿莫西林的生物等效性

目的用有限采样法(LSS)估算口服阿莫西林的生物等效性。方法 20名健康志愿者口服阿莫西林参比药物和受试药物500 mg后采集若干时间点血浆样品,用高效液相色谱法测定阿莫西林血药浓度,用经典方法计算药代动力学参数,评价生物等效性。另以参比药物血药浓度数据作为建模数据,用LSS法估算药代动力学参数Cmax、AUC0-t,选择最佳模型进行生物等效性评价。内外部验证均用Jackknife法。结果以2个和3个血药浓度数据点预测的药代动力学参数回归模型的线性关系较好。内部和外部验证表明:以血药浓度数据2点组合C1,C3和3点组合C1,C2,C4估算AUC0-t的准确性最好(预测误差<1%,绝对误差<10%);又以2点组合C1,C1.5和3点组合C1.5,C2,C6估算Cmax的准确性最好(预测误差<2%,绝对误差<10%);并以3点组合C1.5,C2,C6同时估算AUC0-t和Cmax的准确性较好。与经典法评价结果一致。结论用LSS法估算口服阿莫西林药代动力学参数评价生物等效性是可行的,为有限采样法评价生物等效性提供新的思路和计算方法。

Bioequivalence assessment of amoxicillin by limited sampling strategy in Chinese healthy volunteers

Objective To develop limited sampling strategy(LSS) for estimating bioequivalence of amoxicillin.Methods Twenty male healthy subjects were enrolled in this bioequivalence study.All subjects were divided into two groups randomly and administered orally reference and test formulation of 500 mg amoxicillin.The blood concentrations of amoxicillin were determined by the validated HPLC method.A multiple linear regression analysis was developed for estimating Cmax and AUC0-t using the amoxicillin concentration of the reference formulation to develop LSS models.The LSS models were internally validated by the Jackknife method.The models were also externally validated by bioequivalence assessment of the test amoxicillin formulation based on LSS derived Cmax and AUC0-t values,The results were compared with those obtained using traditional method.Results The results indicate:several models for these parameters estimation met the predefined criteria.Validation tests indicated that most informative sampling points C1,C3 and C1,C2,C4 provided accurate estimations of the parameters AUC0-t.(prediction error<1%,absolute percentage<10%),And C1,C1.5 and C1.5,C2,C6 provided accurate estimations of the parameters Cmax(prediction error<2%,absolute percentage<9%).The combination of C1.5,C2,C6 might be chosen as sampling hours for predicting AUC0-t and Cmax according to requirement.It is according with classical assessment.Conclusion The bioequivalence assessment results showed that LSS models provided correct assessment of bioequivalence between two amoxicillin preparations.The method is accurant and can be considered desirable for amoxicillin bioequivalence study.