基于NONMEM法的华法林群体药动学/药效学模型研究  

Population pharmacokinetic/pharmacodynamic modeling of warfarin by nonlinear mixed effects model

作　　者：林荣芳[1] 林玮玮[1] 王长连[1] 黄品芳[1] 方素君 

机构地区：[1]福建医科大学附属第一医院,福建福州350005 [2]福建医科大学,福建福州350005

出　　处：《药学学报》2015年第10期1280-1284,共5页Acta Pharmaceutica Sinica

基　　金：福建省医药卫生科技创新项目(2014-CXB-13)

摘　　要：本研究旨在建立中国人华法林群体药动学/药效学(PPK/PD)模型。研究中收集接受华法林治疗的73例患者190个血样,PCR-RFLP法检测患者CYP2C9及VKORC1基因分型,RP-HPLC-UV法测定华法林血药浓度。结合临床资料及263个国际标准化比值(INR)监测值,应用NONMEM软件考察患者遗传、生理、病理因素及合并用药等对华法林清除率及抗凝指标的影响,建立了华法林PPK/PD最终模型:CL=θCL·(WT/60)θWT·θCYP·eηCL;EC50=θEC50·θVKOR·eηEC50;V=θV;KE0=θKE0;Emax=θEmax;E0=θE0·eηE0。其中体重、CYP2C9及VKORC1基因分型是影响华法林药动学/药效学参数的主要因素。经拟合优度诊断、Bootstrap法、NPDE验证显示,模型稳定、有效,具有良好的拟合优度与预测能力。Abstract： The study aimed to establish a population pharmacokinetic/pharmacodynamic （PPK/PD） model of warfarin. PCR-RFLP technique was used to genotype the CYP2C9 and VKORC1 polymorphisms of 73 patients. RP-HPLC-UV method was used to determine the 190 plasma concentrations of warfarin. Application of NONMEM, the clinical information and 263 international normalized ratio （INR） monitoring data were used to investigate the effect of genetic, physiological, pathological factors, other medication on clearance and anticoagulant response. The final model of warfarin PPK/PD was described as follows： CL=θCL·（WT/60）θWT·θCYP·eηCL;EC50=θEC50·θVKOR·eηEC50;V=θV;KE0=θKE0;Emax=θEmax;E0=θE0·eηE0Among them, the bodyweight （WT）, CYP2C9 and VKORC1 genotype had conspicuous effect on warfarin PK/PD parameters. The goodness diagnosis, Bootstrap, NPDE verification showed that the final model was stable, effective and predictable. It may provide a reference for opitimizing the dose regimen of warfarin.

关 键 词：华法林 CYP2C9 VKORC1 群体药动学/药效学 

分 类 号：R969[医药卫生—药理学]