有限采样法估算肾病患儿口服咪唑立宾药时曲线下面积模型的建立与验证  

Establishment and validation for estimating the area under the concentration-time curve of mizoribine in children with nephropathy by limited sampling strategy

作　　者：薛源 赵宇蕾[1] 齐谢敏[1] 朱婷婷[1] 黄晓晖[1] 芮建中[1] 周国华[1] XUE Yuan;ZHAO Yu-lei;QI Xie-min;ZHU Ting-ting;HUANG Xiao-hui;RUI Jian-zhong;ZHOU Guo-hua(Department of Pharmacology,General Hospital of Eastern Theater Command,PLA,Nanjing 210002,Jiangsu,China)

机构地区：[1]东部战区总医院(原南京军区南京总医院)药理科,南京210002

出　　处：《医学研究生学报》2020年第9期968-973,共6页Journal of Medical Postgraduates

基　　金：国家自然科学基金(81603219);原南京军区南京总医院科研基金(2011058)。

摘　　要：目的使用传统方法计算药时曲线下面积(AUC0-t)需要多点采集血样,患者依从性差,研究成本过高,不适合在临床使用。文章旨在使用有限采样法估算肾病患儿口服咪唑立宾AUC0-t,并研究咪唑立宾有效性与AUC0-t的相关性。方法收集18例肾病综合征患儿样本,使用高效液相色谱法测定不同时间点的咪唑立宾血清药物浓度,以单点或两点建立血清药物浓度点对AUC0-t的多元线性回归方程,JackKnife法验证模型准确性,采用S形最大效应(Emax)模型考察咪唑立宾有效性与AUC0-t的相关性。结果单点预测采用给药后第3、4、6、8小时的血清药物浓度估算口服MZR的AUC0-t的相关性均较好,回归方程分别为:AUC0-t=5.78 C3(R2=0.95,P<0.05)、AUC0-t=7.23 C4(R2=0.96,P<0.05)、AUC0-t=8.77 C6+3.12(R2=0.95,P<0.05)、AUC0-t=14.40 C8+4.02(R2=0.91,P<0.05),两点预测采用给药后第3和第4小时的血清药物浓度,回归方程为:AUC0-t=2.57 C3+4.18 C4(R2=0.98,P<0.05)。S型Emax模型显示AUC0-t的增加能够提高患儿肾病综合征的复发改善率,Emax=94.20%,EC50=5.70μg/mL,R2=0.89,且AUC0-t的增加降低了患儿尿蛋白水平。结论有限采样法估算肾病患儿口服咪唑立宾AUC0-t结果准确,方法简便。口服咪唑立宾的有效性与AUC0-t存在良好的相关性。Objective Using traditional methods to calculate the area under the concentration-curve(AUC0-t) requires multi-point collection of blood samples, which is not suitable for clinical use due to poor patient compliance and high research cost. This study aims to estimate the AUC0-t of mizoribine(MZR) in children with nephropathy by limited sampling strategy, and to investigate the correlation between MZR’s effectiveness and AUC0-t. Methods Samples of 18 cases of children with nephrotic syndrome were collected and the serum concentrations of MZR at different time points were determined by high performance liquid chromatography(HPLC). The multiple linear regression equation of AUC0-t at serum drug concentration point by single point or two points was established, and then JackKnife method was applied to validate the model’s accuracy, and the sigmoidal biggest effect(E Max) model to investigate the correlation between MZR effectiveness and AUC0-t. Results For single point, there was a good correlation between the AUC0-t of MZR and the serum drug concentration at the 3 rd, 4 th, 6 th and 8 th hours after administration. The regression equations were as follows: AUC0-t =5.78 C3(R2=0.95,P<0.05), AUC0-t=7.23 C4(R2=0.96, P<0.05), AUC0-t =8.77 C6+3.12(R2=0.95,P<0.05), AUC0-t=14.40 C8+4.02(R2=0.91, P<0.05). For two points, the serum drug concentration at the 3 rd and 4 th hours after administration was collected, and its regression equations were as follows: UC 0-t=2.57 C3+4.18 C4,(R2=0.98, P<0.05). Sigmoidal biggest effect(E Max) model shows that the AUC0-t increase can enhance the recurrence period of children with nephrotic syndrome, E Max=94.20%, EC5=5.70 ug/mL, R2=0.89, and reduce their urinary protein levels. Conclusion The limited sampling strategy is simple and accurate for the estimating the AUC0-t of MZR in children with nephropathy and there is a good correlation between the MZR effectiveness and AUC0-t.

关 键 词：咪唑立宾 有限采样法 药时曲线下面积 JackKnife法 有效性 

分 类 号：R97[医药卫生—药品]