Andersons pediatric cardiology 2113
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FutureDirections
PhysiologicallyBasedPharmacokinetics
ModelingandDecisionSupportTools
Theimplementationofpharmacogeneticandpharmacogenomicsintoclinical
practiceischallengingandperhapsevenmorechallenginginourpopulation.
Namely,traditionalallometricscalingfromadultdosescommonlyfailsto
characterizeaccuratedosingrequirementsinapediatricpopulation.118This
continualquandaryofadulttopediatricextrapolationisequallyifnotmore
challenginginapplyingpharmacogenomic-tailoreddosingwherethegenotypephenotyperelationshipobservedinadultsmaynotbeapplicabletothe
developinginfantorchildwithcardiovasculardisease.Giventheknownbarriers
topediatricresearch(e.g.,ethicalconstraints,adequatepowertodetectstatistical
differences,availabilitytoparticipateinresearch,decreasedfunding),119
efficientandfiscallysoundclinicaltrialdesignmustbeperformedtogenerate
accurateandrobustpediatric-specificpharmacogeneticandpharmacogenomic
data.Previousmethodsusingallometricscalingfromadultdosingtoinform
dosingforpediatricpharmacokineticstudieshasledtothediscoverythatcertain
variablesofdrugdispositionand/ordevelopmentwerenotfactoredinthedesign
ofthetrial,thusincreasingtheriskofambiguity.
Physiologicallybasedpharmacokinetic(PBPK)modelsaccountforchangein
physiologyandcovariatesinvolvedindrugdispositionduringchildhoodto
improvethedosingofmedicationinchildren.120PBPKmodelsaremathematical
platformsthatintegratephysiologicparameters(i.e.,organsize,bloodflow)and
drugproperties(i.e.,dissolutionproperties,diffusioncoefficients,protein
binding)todeterminesystemicexposure(Fig.79.5).121Incorporationof
developmentandgeneticvariationintothesemodelsallowspredictionsofdrug
concentrationsinthetissuesresponsibleforresponseandtoxicitysoastomake
themostefficientuseofthelimitedfiscalandhumanresourcesavailablefor
pediatricpharmacotherapy,therebyenhancingfutureclinicaltrialdesignby
reducingthepotentialfortreatmentfailureduetoinadequatesystemicexposure
orexcessivetoxicity.
FIG.79.5 Physiologicallybasedpharmacokineticmodelstructure.
Associatedwitheachcompartment(organsystem)istissuevolume,blood
inflow/outflowrateconstants,andtissueuptakeconstants.EHC,
Enterohepaticrecirculation;IV,intravenous;PO,peroral.
UltimatelytheseconstructswillserveasthefoundationtodevelopPBPKbasedclinicalsupporttoolsforclinicianstooptimizedosingfortheindividual
child(Fig.79.6).122Arecentdecisionsupporttoolcreatedforbusulfan,a
chemotherapeuticagentusedasaregimeninchildreninpreparationofbone
marrowtransplantation,allowsthepoint-of-careprovidertodevelopandverify
appropriateness(e.g.,goodnessoffit)ofapharmacokineticcompartmental
modelbasedonplasmaconcentrationsofthedrug(seeFig.79.6).Following
modeldevelopment,theproviderisabletoconductsimulationsforatargetdose
orexposure.Obviously,thesetypesofclinicalsupporttoolsneedfurther
validation,buttheycouldpotentiallyserveasamechanismbywhichour
communitycouldimplementpharmacogenomicsinavirtualpatientpopulation
priortodosing,thusprovidingmaximalefficacywiththelowestadverse-events
riskprofileinclinicalpractice.
FIG.79.6 Decisionsupporttools.(A)Verificationpage(e.g.,goodnessof
fit)ofapharmacokineticcompartmentmodelbasedonplasma
concentrationsofthedrug.(B)Dose-simulationpagetoconduct
simulationsfortargetdoseorexposurevalues(areaunderthecurveat
steadystate,Cavgss).(FromAbdel-RahmanSM,BreitkreutzML,BiC,et
