群体药动学原理及nonmem法数据分析

NONMEM胡　敏1,张静华1,孙　鹤2,施孝金1,钟明康1(1.,200040;2.,)[](TDM),,[1],(populationpharmacokinetics,PPK),,,Bayes,,,TDMPPKNONMEM[];NONMEM;[]R969.1[]A[]1671-2838(2002)04-0227-04PrincipleofpopulationpharmacokineticsanddataanalysisbyNONMEMmethodHUMin1,ZHANGJing-Hua1,SUNHe2,SHIXiao-Jin1,ZHONGMing-Kang1(1.DepartmentofClinicalPharmacy,HuashanHospital,FudanUniversity,Shanghai200040,China;2.FoodandDrugAdministration,Washington,USA)[ABSTRACT]Thecoreoftherapeuticdrugmonitoring(TDM)isindividualizationregime,i.e.takingthepatients'physio-logical,pathological,andenvironmentalfactorsintoaccounttomakesafeandeffectivedosageregimes.Thekeyoftheprob-lemistogetidealindividualpharmacokineticparameters.Populationpharmacokinetics(PPK)isanewmethodtocombineclassicalpharmacokineticswithstatisticalprinciple,andusesparsedatatoestimatepopulationpharmacokineticparameters.WiththehelpofBayesianmethod,wecanestimateindividualparametersrelativelyaccuratelyandoptimizethedosageregime.Theprincipleofpopulationpharmacokineticsanddataanalysismethodsareintroducedinthisarticle.[KEYWORDS]populationpharmacokinetics;NONMEM;modelvalidation[PharmCare&Res,2002,2(4):227-230],,,(TDM)TDM,,[1],(populationpharmacokinetics,PPK),,,Bayes,,,TDMPPK1,,,,,,,()(),1977Sheiner[2](nonlinearmixedeffectmodel,NON-MEM),,,,SheinerFORTRANNONMEM,TDM,,NONMEMTDM,/[3,4]227ISSN1671-2838PharmCare&Res2002Dec;2(4)E-mailPharmCR@yaoxue.netPhn/Fax86-21-65519829[](98BR009)[](1973-),(),,.E-mail:hshpharm@sh163.net2[5,6]:(1)(naivepooleddataapproach,NPD),,,;(2)(twostagemethod,TS),,,;(3)NONMEM,NPDTS,,,,NPDTS,NPD,,TS,,,,NONMEM,(extendedleastsquare,ELS),,[7]:(1)TDM,,,;(2),;(3),,;(4)NONMEM,3NONMEM3.1　扩展的最小二乘法[8]　NONMEMELS,:OELS(,,2)=!ni=1(yi-f(xi,))22u(xi,,)+ln(2u(xi,,)),2,,n;OELS(,,2)2;yi;xi(,);f(xi,),;u(xi,,)xi,,NONMEMOELS(,,2),3.2　建立模型的步骤与方法[9]　NONMEM5,(1)3.2.1　数据检查　NONMEM,(indexplots),:(1);(2);(3),∀#;(4)NON-MEMID(),3.2.2　建立结构模型　,,[3],,,:(1):-:;-:;-:,-(2)(OBJmin):,,OBJmin3.2.3　建立统计学模型　,,[3],,,3.2.4　优化模型　,,,0,,3.2.5　参数检验　,NONMEMELS(ML),OBJmin-2logLmax(FRM),0,(restrictedregressionmodel,RRM),RRMFRM-2logLmax,F,∃2%=0.05,n=1,RRMFRMOBJmin∃20.05,1(3.84),CL228ISSN1671-2838PharmCare&Res2002Dec;2(4)E-mailPharmCR@yaoxue.netPhn/Fax86-21-655198291NONMEMFig1StandardprocedureforbuildingNONMEMmodel,3.3　模型的有效性[9]3.3.1　模型有效性检验的类型　,()(),(1)[10](data-splitting):(2/3)(indexdataset),(validationdataset),,(cross-validation):n-1,1,,:,;(,Jacknife):,n-1,Jacknife,n,,Jacknife!(bootstrap)[11]:,(resam-229ISSN1671-2838PharmCare&Res2002Dec;2(4)E-mailPharmCR@yaoxue.netPhn/Fax86-21-65519829pling),,,,;,,2.5%95%(),,FDA(2),3.3.2　模型有效性检验的指标　(1):,,,1,[12](2)[13]:,,t-,(3)-[14]:,,-,(4)[15]:,,(5)Posterior[16]:,PPK,PPK:[17][18][19][20]A[21][22][23]PPK,NONMEM,PPKTDM,[]1,.[M].:,1991.27-31.2SheinerLB.Estimationofpopulationcharacteristicsofpharma-cokineticparametersfromroutineclinicaldata[J].JPharma-cokinetBiopharm,1977,5(5):445.3.-[J].,1995,22(5):277.4,,.NONMEM[J].,1997,21(3):157.5.[J].,1986,2(1):24.6.[J].,1993,20(4):195.7SheinerLB.Analysisofpharmacokineticdatausingparametricmodels.:Hypothesistestsandconfidenceintervals[J].JPharmacokinetBiopharm,1986,14(5):539.8SheinerLB,BealSL.Pharmacokineticparameterestimatesfromseveralleastsquaresprocedures:superiorityofextendedleastsquares[J].JPharmacokinetBiopharm,1985,13(2):185.9Guidanceforindustry:populationpharmacokinetics[M].Wash-ington:FoodandDrugAdministration,1999.12-14.10RockerEB.Predictionerroranditsestimationforsubset-se-lectedmodels[J].Technometrics,1991,33(3):459.11EtteEI.Stabilityandperformanceofapopulationpharma-cokineticmodel[J].JClinPharmacol,1997,37(6):486.12BrunoR,VivierN,VergniolJC,etal.Apopulationpharma-cokineticmodelforDocetaxel(Taxotere):modelbuildingandvalidation[J].JPharmacokinetBiopharm,1996,24(2):153.13VozehS,MaitrePO,StanskiDR.Evaluationofpopulation(NONMEM)pharmacokineticparameterestimates[J].JPhar-macokinetBiopharm,1990,18(2):161.14BealSL.Validationofpopulationmodel.E-mailtoNONMEMusersparticipants.February2,1994.15WilliamsPJ,LaneJR,CapparelliEV.Directcomparisonofthreemethodsforpredictingdigoxinconcentrations[J].Phar-macotherapy1996,16(6):1085.16,.3[J].,1993,28(8):475.17,.NONMEM[J].,1994,15(3):267.18,,.NONMEM[J].,1994,15(1):39.19,,,.NONMEM[J].,1996,31(12):881.20,,,.NONMEM[J].,1995,30(3):172.21,,,.NONMEMA[J].,1995,30(4):241.22,,,.[J].,1998,18(1):12.23,,,.[J].,2000,9(1):33.[]2002-04-15[]2002-08-30[]230ISSN1671-2838PharmCare&Res2002Dec;2(4)E-mailPharmCR@yaoxue.netPhn/Fax86-21-65519829