阿奇霉素成人药动学数据外推至儿科人群中的PBPK模型与异速生长模型的比较研究  

A Comparative Study of PBPK Model and Allometric Growth Model of Azithromycin in Extrapolation of Adult Pharmacokinetic Data to Pediatric Population

作　　者：梁露花[1,2] 秦凌峰 詹地富 魏一鸿 姜希伟 肖珅[1,2] 翟菲 LIANG Lu-hua;QIN Ling-feng;ZHAN Di-fu;WEI Yi-hong;JIANG Xi-wei;XIAO Shen;ZHAI Fei(Shenyang Pharmaceutical University,Shenyang 110016,China;Medical Big Data and Artificial Intelligence Engineering Technology Research Center of Liaoning,Shenyang 110016,China)

机构地区：[1]沈阳药科大学,沈阳110016 [2]辽宁省医药大数据与人工智能工程技术研究中心,沈阳110016

出　　处：《中国药学杂志》2020年第17期1470-1475,共6页Chinese Pharmaceutical Journal

基　　金：基金资助:辽宁省自然科学基金项目资助(20180550345,20180550823)。

摘　　要：目的通过建立阿奇霉素的成人-儿童转化模型,为儿科临床用药提供指导性的建议,降低儿童用药风险,实现儿童临床个性化用药。方法查阅相关文献,利用成人的临床阿奇霉素口服给药试验的受试者生理参数结合阿奇霉素的药物特异参数,通过建立异速生长模型,生理药动学(physiologically based pharmacokinetic,PBPK)模型,根据文献提取的儿童个体口服阿奇霉素临床数据验证这2个模型的参数缩放公式的正确性。进一步利用这2种模型模拟出儿童相关药动学参数并计算出这些参数的相对偏差和相对标准误差。结果通过模拟发现2个模型得到的药动学参数cmax、tmax、AUC0-∞实测值接近,都在文献范围内,可认为2模型的参数转化公式正确。进一步计算参数的相对偏差和相对标准误差,成人-儿童PBPK预测模型的cmax、tmax、AUC0-∞的相对偏差和相对标准误差都比异速生长模型的小。结论阿奇霉素PBPK模型预测儿童药动学参数较异速生长模型要好。本研究所应用的口服用药成人-儿童模型特异性参数的缩放公式,经阿奇霉素验证成功,可以外推至其他药物,为其他口服给药的成人-儿童模型转化提供便利。OBJECTIVE To establish an adult-pediatric transformation model of azithromycin to provide guiding recommendations for clinical using of pediatrics,reduce the risk of medicationfor children,and achieve clinical personalized medication for children.METHODS The relevant literature was reviewed.The physiological parameters of the azithromycin oral administration test in adults combined with the drug-specific parameters of azithromycin were used to establish an allometric growth model,PBPK model.According to the clinical data of oral azithromycin extracted from individual children,the correctness of the parameter scaling formulas of these two models was verified.These two models were further used to simulate the pharmacokinetic parameters of children and calculate the relative deviation and relative standard error of these parameters.RESULTS Through simulation,it is found that the pharmacokinetic parameters cmax、tmax、AUC0-∞obtained by the two models are close to the measured values,which are all within the scope of the literature.It can be considered that the parameter conversion formulas of the two models are correct.Further,the relative deviation and relative standard error of the parameters are calculated,and the relative deviation and relative standard error of the adult-pediatric PBPK prediction model are smaller than those of the allometric growth model.CONCLUSION The azithromycin PBPK model predicts that children′s pharmacokinetic parameters are better than the allometric growth model.The scaling formula for the specific parameters of the oral-dose adult-child model used in this article,which was successfully verified by azithromycin,can be extrapolated to other drugs to facilitate the conversion of other oral-adulterated adult-pediatric models.

关 键 词：阿奇霉素 PK-SIM软件 PBPK模型 异速生长 

分 类 号：R969.3[医药卫生—药理学]