APPLICATION-OF-PKPD-MODELING-IN-DRUG-DEVELOPMENT数学

APPLICATIONOFPK/PDMODELINGINDRUGDEVELOPMENTObjectivesofEarlyDrugDevelopmentIdentificationofcriticalriskfactorspriortoinvestmentinfullclinicaldevelopmentselectionofbettercompoundsProvidecriticaldatatoidentifysafeandeffectivedoseanddoseregimensmoreefficientdevelopmentNewParadigminDrugDevelopmentPK/PDindose-rangingproofofefficacystudyinpatients(POC)ConfirmPDinthepivotalstudiesPK/PDinpatients&/orinexperimentalmodelsinhealthysubjects(POM)NewDrugApplicationPost-marketingcomparativePK/PDinpatientsWhyStudyPK/PD?Characterizetimecourseofpharmacologicresponse(therapeutic&/ortoxiceffects)Understandcomplexrelationships–tolerance,sensitization,mechanisticdelayExplainvariabilityinresponseIdentifybiomarkersandvalidatesurrogateendpointsAiddose/doseregimenselectionthroughsimulationBridgeclinicalefficacyandsafetyresultsacrossethnicpopulationsBridgeclinicalresultsbetweenadultandpediatricpatientsRequirementstoCharacterizePK/PDRelationshipValidatedbiomarkersfortherapeuticeffects&toxicity–Shouldbemeaningful(relatestoMOA),reproducible,quantitativeandallowsfrequentsamplingtocharacterizethetimecourseofeffect–ValidatedAssay(reproducible,highprecision….)–Exposure-responserelationshipUnderstandingofpharmacologicbehaviorofthedrugandpathophysiologyofthedisease–PharmacologyandpharmacokineticmodelingModelingDirectResponsesPharmacodynamicsnpnpoCECCEEEn+±=50max.E=Eo±S.lnCP)()().(50maxTpTTpoCCCECCCEEE-+--±=E=Eo±S.CPStaticFunctionsRelatedtoHillEquationConcentration/EC500.0010.010.111010010000.00.20.40.60.81.0Eq1Eq2Eq3Eq4ExamplesofdirectPDeffectwithequilibrationdelay:CNSeffectsofbenzodiazepines&anesthetics;MuscleRelaxantsofd-tubocurarineComplexitiesinPK/PDModelingEquilibrationdelayMechanisticdelayToleranceSensitizationActivemetabolitesDruginteractionModelingIndirectResponsesBiosignalkinkoutRCpVcCLDrugkeoCen).()(50max1neeCECCEtHn+±=outinokkR/=Pharmacodynamics(mechanisticdelay)Daynekaetal.,JPB,1993Juskoetal.,JPB,1995Sharma&Jusko,JPB,1996Sharma&Jusko,BJCP,1998=-=nitieAiCp1..l).(epeoeCCkdtdC-=Pharmacokinetics(equilibrationdelay)RktHkdtdRoutin.)(.-=RtHkkdtdRoutin).(.-=Examples:Anticoagulantseffectsofwarfarin;Gene-mediatedeffectsofcorticosteroidsExamplesIL12:Toleranceinefficacy&safetybiomarkerresponse(IFNg).CD4mAbs:Validateasafetybiomarkerinthepreclinicaltransgenicmicemodel.IL5mAb:Biomarker(eosinophil)isnotavalidatedsurrogateendpoint.P38MAPK:Characterizeanexperimentalmodelofacuteinflammationforanti-TNFresponse.Avitriptan:Characterizesafetyprofile(BPandheartrate).PopPK/PDapproachinLinezolidbridgingprogram.IL12:AnexampleofcomplexPK/PDrelationshipIL12A70kDaheterodimercytokine(35+40kDasubunits).EnhancesThelper1-typeimmunity.PotentiatessecretionofIFNgby,andthecytolyticactivityof,NKcellsandCTLs.IL12-inducedsecretionofIFNgisrequiredforactivity.mIL12haspotentantitumor&antimetastaticactivityinmurinetumormodels.Underdevelopmentforcancerandinfectiousdiseases.PhaseIStudyDesignOpenlabeldose-escalationstudyincancerpatients.AsingledoseofrhIL12followedbycyclesof5consecutivedailyivinjectionatthesamedoseevery3weeks.MTDof500ng/kgwasestablishedinthisstudyAtkinsetal,ClinCancerRes.199711516171819Days2weekswashoutRepeatevery3weeksPhaseIIStudyDesignOpenlabelrepeat-doseefficacystudyinpatientswithadvancedrenalcellcarcinoma.Cyclesof5consecutivedailyivinjectionatMTD(500ng/kg)doseevery3weeks.Leonardetal.,Blood,19972728293031Days3weekswashoutRepeatevery3weeks12345PhaseIIStudyResultsTreatmentwasassociatedwithunexpectedseriousadverseevents.MostofthepatientsexperiencedseriousAEsafter2ndand3rddoses.Twopatientsdiedandnooneenteredthe2ndcycleduetodrugrelatedtoxicitysuchasGIbleeding.PKprofilesforIL12werecomparabletothoseobservedinPhaseIstudy.Leonardetal.,Blood,1997Leonardetal.,Blood,1997Reasonforunexpectedtoxicity:Afour-foldhighertroughIFNgconcentrationsinPhaseIImayhavecausedtheserioustoxicity.SummaryIfIFNgconcentrationswereusedasasafetybiomarker,itwouldhavebeenpossibletoavoidseriousAEsbystoppingafter2nddoseinPhaseIIstudy.AsingledoseofIL12causestoleranceinitsabilitytoinduceIFNgproductionuponfurtherdosing.IL12producestolerancerapidly(3-4days)duringmultipledosingwhichlastsforarelativelylongtimeperiod(14days)inhumans.PK/PDmodelingtocharacterizeschedule-dependentIL12-inducedIFNgproductioniscrucialfordesigningsafeandeffectivedosingregimens.ComparativePDofAnti-CD4mAbsinTransgenicMiceSharmaetal.,JPET,2000Anti-CD4mAbsMediatetheirimmunomodulatoryeffectsviaindirectresponsemechanisms:–removalofCD4+Tcellsviaeffectormechanism;–down-modulationofcellsurfaceCD4viainternalizationorstrippingand/or–inhibitionofCD4-MHCIIinteractions.Underdevelopmentforautoimmunedisordersuchasrheumatoidarthritis.Anti-CD4mAbsKeliximabCynomolgusMacaqueV-domainHumanCl-domainHumang1CH-domainsCH3HCH1CH2HCH3CH1CH2VLVHVHVLVHVH•Primate/humanchimericCD4mAbofIgG1isotype.•Doesnotmediatecomplementdependentcytotoxicity.•ExhibitsefficientbindingtohumanIgGFcreceptorsandcancausedepletionofCD4+cells.ClenoliximabCynomolgusMacaqueV-domainHumanCl-domainHumang4CH-domainsPheLeuGlyGlyProSer235240Glu