Andersons pediatric cardiology 2104
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PharmacogeneticsintheTreatmentof
CongenitalandAcquiredCardiac
DiseaseDuringChildhood
JonathanWagner
Abstract
Asmedicinemovesclosertoaneraofprecision-guidedtherapy,
pharmacotherapywillbeacornerstoneofthisinnovation.
Pharmacokinetics,pharmacodynamics,andpharmacogenomicsarethe
instrumentsbywhichourfieldcanexecuteprecision-guidedtherapyforthe
individualpediatricpatient.Beforegenetictestingisperformedforvariants
relatedtodrugresponse,onemustensurethatvariableresponseisnot
secondarytopoorsystemicexposure.Thereforeafullreviewofthegene
productsthatarequantitativelyimportantinthedrug'sdisposition
(absorption,distribution,metabolism,excretion)mustbereviewedand
investigated.Pediatriciansareuniquelyprimedtounderstandthese
instrumentsowingtoourexperiencewithphysiologicdevelopmentand
genetics.Precision-guidedpharmacotherapeuticsisessentialtoimprovethe
outcomesofcongenitalandacquiredheartdiseaseduringchildhood.
Keywords
cytochromep450;ontogeny;pharmacogenetics;pharmacogenomics;
pharmacokinetics;transporters
Introduction
Pediatriccardiologyproviderscommonlyobservevariableresponsesto
cardiovascularpharmacotherapyand,asaresult,inconsistentorcounterintuitive
outcomesincongenitalandacquiredheartdisease.Thecontributionof
developmentand/orgeneticvariationtotheobservedvariabilityin
cardiovasculardrugdispositionandresponseinchildhoodrequiresfurther
investigationandclarity.Intheabsenceofdatathatareapplicabletothe
individualchild,providersmakingclinicaldecisionsmustoftenrelyondata
generatedinadults.However,itisuniversallyappreciatedinourspecialtythat
growthanddevelopment(ontogeny)canpotentiallyinfluencethediagnosisand
treatmentofclinicaldiseaseduringchildhood.Ontogenyisequallyimportant
whendiscussingpediatricdrugdispositionandresponse.1Therefore,drawing
thesameconclusionsor,potentiallyworse,extrapolatingadultpharmacogenetic
and/orpharmacogenomicsdatatothepediatriccohortmustbeperformedwith
caution.2,3
Geneticvariationisinvariablyassociatedwiththepioneereffortstodeliver
“precisionmedicine.”4However,theprovidermustrecognizethatgenetic
variationremainsonlyonepatient-specificfactorsthatmayinfluencedrug
dispositionandresponse.Thephysiologicprofileoftheindividualpatient(e.g.,
Fontancirculation),formulationofthedrug(e.g.,tabletvs.liquidpreparation),
and/orenvironmentalfactors(e.g.,diet)mustbetakenintoconsiderationwhen
providingprecision-guidedtherapy.5Notwithstanding,forthepurposeofthis
chapter,theprimaryemphasiswillbeontheinfluenceofpharmacogeneticson
thetreatmentandoutcomeofpediatriccardiovasculardisease.
