001-基于体外数据模拟和预测体内PK

page1PKSimulation&PredictionwithIVIVE:InVitroInVivoExtrapolationPharmoGo2014Opage2HowtoPredictPKwithGastroPlusIVIVEapproachpage3Whypredictpharmacokinetics?投入资金高研发周期长药物研发的成功率较低CombinedR&Dsurvivalbydevelopmentphasefor14largepharmaceuticalcompanies(Abbott,AstraZeneca,Bayer,Bristol-MyersSquibb,Boehringer-Ingelheim,EliLilly,GlaxoSmithKline,Johnson&Johnson,Merck,Novartis,Pfizer,Roche,Sanofi-AventisandSchering-Plough)MarkEBunnage.GettingpharmaceuticalR&Dbackontarget.NatureChemicalBiology.2011,7:335–339.page4MethodstopredictpharmacokineticsAnimalMethodsAllometricscalingInvitroMethodsIVIVEMechanisticalmodelsPBPKInSilicoMethodsDiscoveryDevelopmentTime-consumingandcostlyendeavorPredictionHumanPKpropertiespage5AllometricscalingPK决定因素不同生理解剖体系代谢基因型和表型组织成分如蛋白种类直接放大，误差极大Toobtain“a”and“b”:plotthebodyweightofthespecies(atleast3species)vsparameterofinterestsuchasclearancepage6IVIVEvs.AllometricscalingOldParadigm：Useinvivoanimalmodelasthepredictorofhumanbehavior(eg.allometricscaling)NewParadigmUsepredictive,relevantinvitrodatathatwillfeedthemodelforpredictinginvivobehaviorIVIVE:体外体内转化（InVitroInVivoExtrapolation）page7Empiricalmethodvs.PBPK:page8ParametersdescribePKprofileVolumeofdistributionClearanceAbsorptionHalf-lifeBioavailabilityDosingregimen：Howoften？Dosingregimen：Howmuch？page9*ModifiedfromvandeWaterbeemd,H,andGifford,E.ADMETInSilicoModelling:TowardsPredictionParadise?Nat.Rev.DrugDisc.2003,2:192-204F(notFa!)FaDPVFDp(notFa!)AbsorptionMetabolismMetabolismASCModern(FDA)DefinitionofAbsorptionWhatisFractionAbsorbed(Fa)?page10ACATModelBrainAdiposeMuscleSkinEachphysiologyincludesdefaultvaluesfor:•pHineachcompartment•Transittimeforeachcompartment•Lengths&radiiofeachcompartment•SEFsofeachcompartment•Stomachvolume•Bilesaltconcentrationineachcompartment•Poresizeineachcompartment•Porosity/PoreLengthineachcompartment•Hepaticbloodflowrate•Gutenzymeandtransporterdistributionspage11Absorptiontermincompartmentnumberi:ASFtrans,IandASFpara,i=transcellularandparacellularabsorptionscalefactorincompartmenti(nominalvalueissurface/volume,whichis2/Ri)Ri=radiusofcompartmentiPtrans,iandPpara,i=transcellularandparacellularpermeabilityincompartmenti*Vlum,i=volumeoflumenforcompartmentiC(t)lum,i=lumenconcentrationincompartmentiC(t)entU,i=unboundenterocyteconcentrationincompartmentiC(t)pvU=unboundportalveinconcentrationpvUilumilumiparaiparaientUilumilumitransitransiabstctcVPASFtctcVPASFdtdM)()()()(,,,,,,,,,,AbsorptionKa’Mdiss(i)RiLiAbsorptionscalefactors(ASF)accountforchangesinabsorptionduetoregionaldifferencesinradius,ionization,tightjunctiongap,andcarrier-mediatedtransport.page12Threeprimarypropertiesofadrug/dosageformcanlimitabsorptioninthegastrointestinaltract:SolubilityDissolutionrateIntestinalpermeabilityGastroPlus™simulation：Inputdatarequiredwouldbepreformulationinformation(solubility,permeability,pKa·····)Structure-propertypredictions(fromADMETPredictor™)provideestimatesfor:pKa,logP,solubility,permeability,etc.AccuratephysiologicalsituationsaretakenintoconsiderationSolubility,Dissolution,andPermeabilitypage13TotalamountdissolvedTotalamountabsorbedTotalamountintosystemiccirculation(bioavailability)TotalamountintoportalveinAbsorptionpage14Structure-propertypredictions(fromADMETPredictor™)provideestimatesfor:pKa,logP,solubility,permeability,plasmaproteinbinding,etc.Kp’sestimatedfromlogPorlogDandtissuepropertiesActivitylogPpKaSolubilityatreferencepHHumanjejunalpermeabilityVolumeofdistributionPlasmaproteinbinding,fupToxicities...etc.QSPRDistribution：KpPartitioningintotissues：Kpbindinglipidpartitioningtransportother??page15DistributionSteadystatevolumeofdistributionisestimatedusingthetissuevolumesandtissue:plasmapartitioncoefficientsaccordingtoPoulin:𝑽𝒔𝒔=𝑽𝒑+𝑽𝒆∗𝑬:𝑷+𝑽𝒕∗𝑲𝒑𝒕∗(𝟏−𝑬𝑹𝒕whereVpisvolumeofplasma,Veiserythrocytevolume,E:Piserythrocytetoplasmaconcenctrationratio(calculatedfromblood/plasmaconcentrationratioandhematocrit),Vtistissuevolume,Kptisthetissue:plasmapartitioncoefficient,andERtistheextractionratioforagiventissue.Where,𝑬:𝑷=(𝑹𝒃𝒑−(𝟏−𝑯𝒕))𝑯𝒕𝑬𝑹=𝒇𝒖𝑪𝑳𝒊𝒏𝒕𝑸+𝒇𝒖𝑪𝑳𝒊𝒏𝒕page16ClearanceInGastroPlus,thetotalclearance,CL,isthesumofclearancefromeveryeliminatingorgan;Butmainlyhepatic(CLH),renal(CLR),andbiliary(CLB):𝑪𝑳=𝑪𝑳𝑯+𝑪𝑳𝑹+𝑪𝑳𝑩page17Step1.Invitroincubationofdrugwithmicrosomes/hepatocytes/liverslicestoobtainenzymekineticconstantsVmaxandKmandtheinvitrointrinsicclearanceStep2.Scaleinvitroenzymekineticconstantstoinvivoconditionsbasedonspecies-specificphysiologicalscalefactors.CLintinvitroCLint(wholeorgan)invivoCLh(wholeorgan)invivoStep3.Basedonahepaticbloodflowmodel(e.g.Venousequilibriummodel),determineinvivohepaticclearance.Rateofdrugelimination=CLh×ConcentrationClearance：hepaticpage18LiverMetabolismRate=CLh*CliverCLh=Eh*Qh*RBEh=CLinth*fu,plasma/[CLinth*fu,plasma+Qh*RB]whereCLinth=ΣVmax(j)*Cu,hepat/(Km(j)+Cu,hepat)Eh=totalhepaticextractionQh=hepaticbloodflowrateRB=blood-to-plasmaconcentrationratioCLinth=totalhepaticintrinsicclearanceVmax(j)=maximummetabolicrateforenz