同种异体肾移植受者围术期卡泊芬净群体药动学及药效学研究  

Population pharmacokinetics and pharmacodynamics of caspofungin in renal allograft recipients during perioperative period

作　　者：凌静[1] 钱卿[1] 胡楠[1] 杨旭萍 陈荣[1] 蒋艳[1] 邹素兰[1] LING Jing;QIAN Qing;HU Nan;YANG Xuping;CHEN Rong;JIANG Yan;ZOU Sulan(Department of Pharmacy,The First People's Hospital of Changzhou,Jiangsu Changzhou 213003,China)

机构地区：[1]常州市第一人民医院药学部,江苏常州213003

出　　处：《中国医院药学杂志》2024年第6期611-618,共8页Chinese Journal of Hospital Pharmacy

基　　金：江苏省药学会-奥赛康医院药学基金项目(编号:A202021)。

摘　　要：目的:建立异体肾移植受者围术期静脉用卡泊芬净的群体药动学(population pharmacokinetics,PPK)模型,探讨并优化卡泊芬净用于治疗念珠菌属的剂量方案。方法:前瞻性收集常州市第一人民医院行同种异体肾移植术且术后静滴注射用醋酸卡泊芬净的51例受者共计134次血药浓度监测数据,考察的协变量包括年龄、性别、体质量(body weight,WT)、体质量指数,及谷丙转氨酶、谷草转氨酶、总胆红素、血浆白蛋白、血清肌酐、胱抑素C(serum cystatin C,Cys C)等临床指标,采用非线性混合效应模型程序(nonlinear mixed effect method,NONMEM)建立卡泊芬净的PPK模型,并采用自举法(Bootstrap)和正态化预测分布误差法(normal prediction distribution error,NPDE)进行模型验证。另采用Crystal Ball软件进行蒙特卡洛模拟,根据AUC_(0-24)/MIC计算不同剂量方案的达标概率(PTA),当PTA>90%时,判定为抗菌疗效良好。结果:基础模型采用一级消除的一室模型,WT和Cys C是影响卡泊芬净清除率(CL)的主要协变量,最终模型为CL(L·h^(–1))=0.411×(Cys C/3.17)~(–0.277)×(WT/57)~(0.519),分布容积(V)=10.7 L。Bootstrap法验证模型可靠稳定,且NPDE结果显示模型的预测能力较好。蒙特卡洛模拟显示,对于白色念珠菌(MIC_(90)=0.06 mg·L^(–1))和光滑念珠菌(MIC_(90)=0.125 mg·L^(–1)),各设定WT(40,60,80 kg)和设定Cys C(1,5,10 mg·L^(–1))下的不同剂量(50~150 mg·d^(–1))方案均可实现PTA>90%。对于近平滑念珠菌(MIC_(90)=1 mg·L^(–1)),所有剂量方案均不能达到药效学靶标。结论:在肾移植受者群体中初步建立了卡泊芬净的PPK模型,临床应用该模型结合患者的WT、肾功能状态,念珠菌种类和MIC值水平科学地制订个体化的给药方案,可达到改善临床结局、减少不良反应的目的。OBJECTIVE To establish population pharmacokinetics(PPK)model of caspofungin and investigate appropriate dosing optimization against Candida spp.in renal allograft recipients during perioperative period.METHODS Totally 134 blood concentration monitoring data were prospectively collected from 51 renal transplant recipients who received caspofungin intravenously.The covariates investigated include age,gender,body weight,body mass index,alanine aminotransferase,aspartate aminotransferase,total bilirubin,albumin,serum creatinine,serum cystatin C and other biologic al parameters.PPK model was established by nonlinear mixed effect model method.Bootstrap method and normal prediction distribution error(NPDE)method were adopted for internal validation of model.Monte Carlo simulations were performed using Crystal Ball software,and the likely success of treatment identified with the probability of target attainment(P TA)by comparing the pharmacodynamic exposure against minimum inhibitory concentration(MIC)distribution.The regimens had an optimal success of fungistatic effect if PTA>90%.RESULTS The pharmacokinetics of caspofungin was best described by a one-compartment model with first-order elimination.Body weight(WT)and serum cystatin C(CysC)had significant influence on caspofungin clearance from covariate analysis.The final model was CL(L·h^(-1))=0.411×(CysC/3.17)-0.277×(WT/57)0.519,V(L)=10.7.The PPK model was validated to be reliable and stable by Bootstrap method,and the NPDEs indicated a good fit of the model to the individual data.The results of simulations predicted that various drug regimens(50~150 mg·d^(-1))may have a high probability of successful outcome against C.albicans(MIC_(90)=0.06 mg·L^(-1))and C.glabrata(MIC_(90)=0.125 mg·L^(-1))with a broad range of WT(40~80 kg)and CysC(1~10 mg·L^(-1)).However,none of the dosage regimens of caspofungin achieved an expected fungicidal target for C.parapsilosis(MIC_(90)=1 mg·L^(-1)).CONCLUSION This study established a PPK model of caspofungin in the renal transplant

关 键 词：肾移植 卡泊芬净 群体药动学 蒙特卡洛模拟 

分 类 号：R969.1[医药卫生—药理学]