氟比洛芬酯活性代谢物氟比洛芬的群体药动学研究

Population pharmacokinetic modeling of flurbiprofen

本研究旨在建立氟比洛芬酯(FA)活性代谢物氟比洛芬(FP)群体药动学模型。研究中前瞻性采集23例颌面外科和耳鼻喉科全麻手术患者静脉注射FA后12 h内的246个血样,高效液相色谱法测定FP浓度,同时收集患者临床资料,利用NONMEM软件进行群体药动学数据分析。Bootstrap重复抽样用于模型的内部验证,视觉预测评估法用于模型的外部验证。数据符合二房室模型,体重(WT)对FP中央室相对清除率(CL)及中央室分布容积(V1)均有显著影响,性别(Gender)、年龄(Age)、给药剂量(TAMT)均不影响FP的药动学参数。FP的基础模型为:CL(L.h?1)=1.28×EXP(ETA(1)),V1(L)=5.03×EXP(ETA(2)),Q(L.h?1)=8.5×EXP(ETA(3)),V2(L)=4.39×EXP(ETA(4));最终模型为:CL(L.h?1)=1.32×(WT/60)×EXP(ETA(1)),V1(L)=5.23×(WT/60)×EXP(ETA(2)),Q(L.h?1)=8.45×EXP(ETA(3)),V2(L)=4.37×EXP(ETA(4))。CL、V1、Q、V2的群体典型值分别为1.32 L.h?1、5.23 L、8.45 L.h?1和4.37 L。Bootstrap重复抽样和视觉预测评估法显示所建立的最终模型稳定、有效、且有较好的预测效能。根据患者的生理用药资料,结合上述模型,可估算个体药动学参数,为临床个体化给药提供依据。

The paper is to report the establishment of a population pharmacokinetic model for flurbiprofen（FP）,an active metabolite of flurbiprofen axetil（FA）.246 FP serum concentration and clinical data were perspectively collected from 23 general anaesthesia patients receiving FA intravenously before operation in Dentofacial Surgery and Otorhinolaryngology Department of the First Affiliated Hospital of Fujian Medical University.Population pharmacokinetic data analysis was performed using NONMEM software.The measure of Bootstrap was applied for internal validation,while Visual Predictive check was adopted for external validation.The data of FP correspond with two-compartment model.The body weight（WT） had conspicuous effect on clearance and volume of central compartment,while sex,age and daily dose of administration had no marked effect on pharmacokinetic parameter of FP.The basic model was described as follows： CL（L.h？1） = 1.28× EXP（ETA（1））,V1（L） = 5.03× EXP（ETA（2））,Q（L.h？1） = 8.5×EXP（ETA（3））,V2（L） = 4.39×EXP（ETA（4））.The final model was described as follows： CL（L.h？1） = 1.32×（WT/60）×EXP（ETA（1））,V1（L） = 5.23×（WT/60）× EXP（ETA（2））,Q（L.h？1） = 8.45×EXP（ETA（3））,V2（L） = 4.37×EXP（ETA（4））.The population typical value of CL,V1,Q and V2 were： 1.32 L.h？1,5.23 L,8.45 L.h？1 and 4.37 L,respectively.Bootstrap and visual predictive check show that the final model of FP is stable,effective and predictable.A novel population pharmacokinetic model is developed to estimate the individual pharmacokinetic parameter for patients intravenous injecting FA