群体药代动力学_群体药效动力学原理及研究方法

183Vo.l18No.320053JournalofMedicalPostgraduatesMar.2005群体药代动力学/群体药效动力学原理及研究方法芮建中1,张震2,李金恒1(1.,210002;2.,230001):(FDA)!(PK)(PD),/(PPK/PPD)PPK/PPD:;;:R969.1:A:10088199(2005)03024604*TheprinciplesandapproachesofpopulationpharmacokineticsandpopulationpharmacodynamicsRUIJianzhong1,ZHANGZhen2reviewing,LIJinheng1checking(1.DepartmentofClinicalPharmacology,NanjingGeneralHospitalofNanjingMilitaryCommand,PLA,Nanjing210002,Jiangsu,China;2.DepartmentofPharmacy,AnhuiProvincialHospital,Hefei230001,Anhui,China)Abstract:Sincepopulationpharmacokinetics/pharmacodynamics(PPK/PPD)werepermittedforevaluatingPK/PDofnewdrugsinphaseandphase!clinicaltrialsaboutspecialphysiopathologicalsubjectsbyFDA.Thenewdevelopmentofitsprinciples,statisticanalysis,usefulsoftwareandapplicationsinclinicalpharmacologyweremarked.Andthebasicconceptions,experimentaldesign,modelingdefinitionandparameterverificationofPPK/PPDwereintroduced.Keywords:Populationpharmacokinetics;Populationpharmacodynamics;Nonlinearmixedeffectmodel0/(Populationpharmacokinetics/pharmacodynamics,PPK/PPD)PKPD,PK/PDPPK/PPD,,,PKPD1998(FDA)[1]!PK/PD,PPK/PPDPPK/PPD11.1PPKPK,(PPK,246*:20040703;:20040916:(1964),,,,,,),PK,1.2PPDPD,,(PPD),1.3群体典型值(typicalpatient),(),()1.4确定性变异,1.5随机性变异(),;2(standardtwostage,STS):PK/PD,;,,(iterativetwostage,ITS):,Bayes;,;,;(nonparametricmethods,NPM):,;(NPML)(NPEM)(SNP)(NONMEM)[2]:PKPDPKPD,;,;,,NONMEMPPK/PPD,,FDA33.1数据收集3.1.1数据的准确性,,,(prospectiveanalysis),,3.1.2数据的完整性,,,,;;(,);;,PKPD,,;;,,3.2取样设计3.2.1样本数,10050,,3.2.2取样点数2~4,:PKPD;,,3,2,,3.2.3取样时间,,,,3.3注意事项,,,,2473,/,,;PKPD4NONMEM4.1PK模型PK4.2PD模型PDSEmax4.2.1PKPD结合模型,,PKPD(PKPD),PPKPPDKeo,(PPKPD)[3]4.2.2特殊机制PD模型,CeE,,,PKPD[3]4.3固定效应模型4.3.1线性模型L=1+2CrCljL,1(),,;CrClj,2(),4.3.2乘法模型^CL=1CrCl2j4.3.3饱和模型^CL=1-2Css23+Css2CSS2,,234.3.4指示变量模型^CL=12HFHF(heartfailure),1,0,4.4随机效应模型PKPD,P4.4.1加法模型Pj=^P+PjPj,^P,Pj,!2P4.4.2对数加法模型ln(Pj)=ln(^P)+Pj4.4.3乘方模型^Pj=^P+^PNPjNN=0,;N=1,0N1,5NONMEM5.1经典PK模型,,PKNONMEM,5.2固定效应模型5.2.1残差散点图观察法,5.2.2POSTHOC与有序递加法PKPD()POSTHOCPKPD,,PKPD,,(),,,,[4]5.2.3假设检验ELS(ML),OBJmin2logLmax5.3随机效应模型5.4时间参数模型PKPD,Karlson(interoccasionvariability,IOV),IOV[5]5.5PD模型,PD,PPD2482005318PPKPDPDEttePPKPPD,,6(),PK/PD,6.1验证类型和方法,,6.1.1数据分割法(datasplitting),(),,,PPK/PPD(crossvalidation)6.1.2自助法(bootstrapping),PPK/PPD6.2验证评判标准6.2.1标准化预测误差(standardizedmeanpredictionerror,SMPE),(meansquaredpredictionerror,MSPE),(meanpredictionerror,MPE)6.2.2模型参数验证法PK/PD6.2.3预测误差百分比(PE%)和绝对预测误差百分比(|PE|%)PE%|PE|%,PE%=(Cpij-IPREDij)/IPREDij,∀PE∀%=∀Cpij-IPREDij∀/IPREDijCPijij,IPREDij6.3结果分析,,,90%95%(CI),,,[6]7PK/PD,,PK/PD,,PK/PD,PPK/PPD,,,PPK/PPD,Bayesian,,PK/PD,PPK/PPD,,NONMEM,,[7,8]:[1]FDAguidelines.Guidanceforindustry:populationpharmacokinetics[M].Washnigton:FDA,1999.1214.[2].[M].:,2003.206242.[3].[M].:,2003.243276.[4],,.A[J].,2002,18(6):431437.[5]LuJF,PfisterM,FerrariPetal.Pharmacokineticpharmacodynamicmodellingofmagnesiumplasmaconcentrationandbloodpressureinpreeclampticwoman[J].ClinPharmacokinet,2002,41(13):11051113.[6]deHoogM,SchoemakerRC,vandenAnkerJNetal.NONMEMandNPEM2populationmodeling:acomparisonusingtobramycindatainneonates[J].TherDrugMonit,2002,24(3):359365.[7]KirchheinerJ,BrockmollerJ,MeinekeIetal.ImpactofCYP2C9aminoacidpolymorphismsonglyburidekineticsandontheinsulinandglucoseresponseinhealthyvolunteers[J].ClinPharmacolTher,2002,71(4):286296.[8]CalliesS,deAlwisDP,HarrisAetal.ApopulationpharmacokineticmodelforpaclitaxelinthepresenceofanovelPgpmodulator,Zosuquidartrihydrochloride(LY335975)[J].BrJClinPharmaco,l2003,56(1):4656.(:鲁立;:唐文杰)2493,/