应用PBPK模型模拟计算国产阿奇霉素颗粒(Ⅱ)的幼儿药物代谢动力学与预测评价  

Application of PBPK Model to Simulate the Pharmacokinetics and Predictive Evaluation of Domestic Azithromycin Granules(Ⅱ)in Young Children

作　　者：张斗胜 姚兰 张亚杰 张庆生 ZHANG Dousheng;YAO Lan;ZHANG Yajie;ZHANG Qingsheng(Institute for Drug Control,National Institutes for Food and Drug Control,Beijing 102629,China;Institute for Drug Control,Liaoning Inspection,Examination&Certification Centre,Shenyang 110036,China)

机构地区：[1]中国食品药品检定研究院化学药品检定所,北京102629 [2]辽宁省检验检测认证中心药品检验检测院,沈阳110036

出　　处：《药学与临床研究》2023年第2期97-103,共7页Pharmaceutical and Clinical Research

基　　金：国家药品监督管理局化学药品质量研究与评价重点实验室开放课题(10300590126)。

摘　　要：目的:计算模拟国产阿奇霉素颗粒(Ⅱ)的幼儿药物代谢动力学(PK)参数并预测评价其安全性和有效性。方法:常规溶出曲线实验拟合得到体外释放曲线,Gastroplus软件搭建生理机制药物代谢动力学(PBPK)模型,结合两者采用群体虚拟技术模拟国产阿奇霉素颗粒(Ⅱ)在幼儿中的PK特征进行安全与有效性预测评价。结果:Korsmeyer-Peppas模型评价国产阿奇霉素颗粒(Ⅱ)与国外阿奇霉素细粒剂的体外溶出曲线具有相似性;威布尔函数拟合显示阿奇霉素在体内的吸收具有饱和性,不受体外溶出差异影响;PBPK模拟主要PK参数包括Cmax(36.2 ng·mL^(-1))、AUC0-t(451.1 ng·h·mL^(-1))、tmax(3.6 h);对比文献报道,计算预测错误系数(PE)分别为2.5%、6.3%和9.1%(均<10%),模型确定系数(Rsq)为0.808(>0.8),表明模型准确可信;而群体药物代谢动力学模拟(PS)预测显示,在90%置信区间(CI)内,Cmax、AUC0-t以及tmax的差异变化较大,其中Cmax和AUC0-t的变异系数(CV)分别达到30.906%和28.25%。结论:国产阿奇霉素颗粒(Ⅱ)与国外阿奇霉素细粒剂的体外溶出差异未影响其体内药物代谢动力学行为;预测评价提示幼儿的生理发育状态会影响肝脏清除率,增加了体内PK参数的个体差异变化风险性,建议给予关注和加强用药指导。Objective:To calculate the pharmacokinetics(PK)by simulation and to predict the safety and efficacy evaluation of domestic azithromycin particles(Ⅱ)in young children.Methods:The release curves in vitro were obtained by fitting the conventional dissolution curve experiments,and the physiologically based pharmacokinetics(PBPK)model was built by the Gastroplus software.The two methods were combined to analyze the PK characteristics of domestic azithomycin granules(Ⅱ)in young children using population simulation technology and to conduct clinical simulation evaluation.Results:The dissolution curves of domestic azithomycin granules(Ⅱ)were similar to those of Japanese azithomycin granules evaluated by the Korsmeyer Peppas model.Weibull function fitting showed that the absorption of azithomycin in vivo was saturated and was not affected by the difference of dissolution in vitro.The main PK parameters simulated by the PBPK model included Cmax(36.2 ng·mL^(-1)),AUC0-t(451.1 ng·h·mL^(-1))and tmax(3.6 h).Compared with the literature reports,the calculated prediction errors(PE)were 2.5%,6.3%and 9.1%,respectively(all<10%),and the model R-square(Rsq)was 0.808(>0.8),indicating that the model was accurate and reliable.The population pharmacokinetics simulation(PS)prediction showed that the difference of Cmax,AUC0-t and tmax changed greatly within the 90%confidence intervals(CI),with the coefficient of variation(CV)of Cmax and AUC0-t reaching 30.906%and 28.25%,respectively.Conclusion:The difference of dissolution in vitro between domestic azithromycin granules(Ⅱ)and foreign azithromycin fine granules did not affect their pharmacokinetic behavior in vivo.The prediction and evaluation indicated that the physiological development status of young children would affect their liver clearance rate and increase the risk of individual differences in PK parameters in vivo.It is suggested to pay attention to and strengthen the medication drug guidance.

关 键 词：生理机制药物代谢动力学 药物代谢动力学 国产阿奇霉素颗粒(Ⅱ) 幼儿 计算模拟 预测评价 

分 类 号：R969.1[医药卫生—药理学]