傅立叶扩展灵敏度分析法在他克莫司群体药物动力学模型中的应用  

Application of Fourier amplitude sensitivity test in Chinese healthy volunteer population pharmacokinetic model of tacrolimus

作　　者：管峥[1,2] 张关敏[3] 马萍[4] 刘丽宏[4] 周田彦[1,2] 卢炜[1,2] 

机构地区：[1]北京大学天然药物及仿生药物国家重点实验室,北京100191 [2]北京大学药学院药剂学系,北京100191 [3]北京大学临床肿瘤学院、北京肿瘤医院暨北京市肿瘤防治研究所,北京100142 [4]中国人民解放军第二炮兵总医院药剂科,北京100088

出　　处：《药学学报》2010年第7期883-890,共8页Acta Pharmaceutica Sinica

基　　金：北京大学综合性创新药物研究开发技术大平台建设基金资助项目(2009ZX09301-010)

摘　　要：本研究应用傅立叶扩展灵敏度分析法(Fourier amplitude sensitivity test,FAST),针对他克莫司的群体药物动力学模型,评价参数的变异度的改变对模型输出值的影响。此外,根据药物动力学参数在不同采血时间点的灵敏度指数变化,设计不同的采样方案,并比较相应拟合参数的质量,以确定不同时间点的预测效力。结果发现,他克莫司群体药物动力学二室模型中除CL1/F外的其他4个参数V1/F、V2/F、CL2/F和ka(吸收速率常数)的灵敏度指数水平较高,随时间的变化速度也较快。另外,随ka变异度的增大,其自身的灵敏度指数明显增加,而其他参数的灵敏度指数显著降低,且CL1/F灵敏度指数的达峰时间发生明显前移。针对仿真数据按不同采样方案进行拟合,发现根据傅立叶灵敏度分析法设计的方案拟合出的数据质量优于其他方案。结果提示,傅立叶扩展灵敏度分析法能够有效检验模型参数的灵敏度,并且可以辅助设计临床采样的较优采样时间,提高模型质量。In this study,we evaluated the influence of different variance from each of the parameters on the output of tacrolimus population pharmacokinetic（PopPK） model in Chinese healthy volunteers,using Fourier amplitude sensitivity test（FAST）.Besides,we estimated the index of sensitivity within whole course of blood sampling,designed different sampling times,and evaluated the quality of parameters＇ and the efficiency of prediction.It was observed that besides CL1/F,the index of sensitivity for all of the other four parameters（V1/F,V2/F,CL2/F and ka） in tacrolimus PopPK model showed relatively high level and changed fast with the time passing.With the increase of the variance of ka,its indices of sensitivity increased obviously,associated with significant decrease in sensitivity index for the other parameters,and obvious change in peak time as well.According to the simulation of NONMEM and the comparison among different fitting results,we found that the sampling time points designed according to FAST surpassed the other time points.It suggests that FAST can access the sensitivities of model parameters effectively,and assist the design of clinical sampling times and the construction of PopPK model.

关 键 词：群体药物动力学 傅立叶扩展灵敏度分析法 他克莫司 非线性混合效应模型 

分 类 号：R969[医药卫生—药理学]