Andersons pediatric cardiology 2112
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Antiarrhythmics
Flecainide,aclass1cantiarrhythmicwithpotentsodiumchannelblockade
propertiesusedinthetreatmentofadultandpediatrictachyarrhythmias,87–95
representsaperfectexampleofanolderdrugutilizedinpediatriccardiology.
Thereis,however,asignificantdearthoffullcharacterizationoftheentiredrug
dispositionpathway.Flecainideismetabolizedinthehepatocytetom-Odealkylatedflecainide(MODF)andsubsequentlyoxidizedtom-O-dealkyalted
lactam(MODLF).Thesetwomajormetaboliteshavelowpotency,withMODF
havingonly20%relativeantiarrhythmicactivityandMODLFhavingno
detectableantiarrhythmicactivity.96,97Invitroandinvivodatasuggestthat
CYP2D6isthemostimportantenzymecontributingtoflecainide
metabolism,97–99andtherehasbeenasignificantdifferenceobservedinAUC,
eliminationhalf-life,andclearanceamongextensivemetabolizers(EMs),
intermediatemetabolizers(IMs),andpoormetabolizers(PMs).99–101Twosmall
studiesfoundthattheCYP2D6phenotype,basedondextromethorphan
metabolicratios,hadnopharmacodynamicseffect(QRSprolongation).102,103
NotablyabsentwastheCYP2D6genotypetospecificallyseparateEMsand
IMs;withthisinformation,achangemayhavebeenappreciated.Additionally,
thesestudieswerecomplicatedbyalownumber(n=4)ofPMs.DPWGdosing
guidelinesrecommenda50%reductionindoseforPMsanda25%reductionfor
IMs.104ClearlytheimpactoftheCYP2D6genotypeonthepharmacodynamics
offlecainiderequiresfurtherelucidationinbothadultsandchildren.CYP2D6
expressionrapidlyincreasesafterbirth,suggestingthatontogenymayplayless
ofaroleforflecainidebiotransformationintheinfantandchild.Asacorrelate,a
pediatricstudyonanotherCYP2D6substrate,atomoxetine,foundthatdespitea
meanAUCdifference(~10-fold)amonggenotypegroupsbeingcomparableto
adultdataintheproductlabel,thereexisteda50-foldrangeofAUCbetweenthe
mostimpairedmetabolizersandthemostrapidmetabolizeradministereda
similarFDA-approvedweight-basedstartingdose(0.5mg/kg).105Thiswide
rangeofpossibleexposureisalarmingwhenappliedtoantiarrhythmics,where
thetherapeuticindexisnarrow.Overall,withtheexperiencewithatomoxetine,
onewouldanticipatethatthesamegenotype-phenotyperelationshipappreciated
intheadultpopulationwithrespecttoflecainidemaynotbeapplicabletothe
developingchild,thuswarrantingfurtherevaluationinapediatriccohortbefore
genotype-drivenrecommendationscanbemade.
Immunosuppression
ArecentpharmacogenomicsreviewbyVanDriestandWebbersummarizesthe
currentpharmacogenomicsliteraturepertainingtopediatriccardiac
transplantation,tailoringmuchofthediscussiontoimmunosuppressive
agents.106Tacrolimus,acalcineurininhibitorutilizedforimmunosuppression
followingsolidorgantransplantation,undergoesdeactivationviaaCYP3A5mediatedoxidativereaction.107Pediatriccardiactransplantpatientswith
CYP3A5*1/*3orCYP3A5*1/*1,functionalgenotype,hadplasmatacrolimus
exposuresthatwere25%and50%ofthosedetectedwiththenonfunctioning
genotypeCYP3A5*3/*3intheimmediate(≤2weeks)and3-to12-month
posttransplantperiod,respectively.108ThisenhancedCYP3A5-mediated
metabolisminpatientswithfunctionalgenotypesledtomuchlowersystemic
exposure,translatingtolargerdoserequirements.Additionally,youngerageis
associatedwithdecreasedtacrolimussystemicexposureandincreaseddosing
requirements.108–111Tacrolimusisoneofthefewexampleswherepediatric
specificCPICguidelinesexistwithrecommendationsthatchildrenand
adolescentswithatleastoneCYP3A5*1allelehavea1.5to2-foldincreasein
doseinadditiontoclosetherapeuticdrugmonitoring.112InthestudybyGijsen
etal.,itwasobservedthatless15%oftacrolimusplasmaconcentrationsinthe
first2weeksaftercardiactransplantationwereinthetherapeuticrange.108This
inadequatedosinghighlightstheneedforprospectivepharmacogenomics-driven
trialsaimedatdeliveringmoreappropriatetacrolimusplasmaconcentrationsto
improveimmunosuppressioninthisvulnerablepopulation.
Antihypertensives
Angiotensinconvertingenzymeinhibitors(ACEIs)remainamongthemost
commonlyusedcardiacmedicationsinpediatriccardiologyforhypertensionand
afterloadreductioninpatientswithsingle-ventriclephysiologyandventricular
dysfunction.Enalapril,administeredinitsinactiveprodrugform,undergoes
rapidhepaticmetabolismviaesterasestoformitsactivemetabolite,
enalaprilat.113Similartoflecainide,enalaprilrepresentsanotherolderdrugused
inpediatriccardiologyforwhichlittleornodataregardingdrug
biotransformationortransportexist.Whenfacedwiththeseinstances,initialin
vitrostudiesmustbedesignedtocharacterizethedrugdispositionpathways.
Oncedetermined,invivoandpediatricgenotype-stratifiedpharmacokinetic
studiescanbeperformedtodeterminetheimportanceofthosepathwaysand
fullycharacterizetheanticipatedextremesofthedose-exposurerelationship.In
vitro,enalaprilundergoesOATP1B1-mediateduptakeintothehepatocytefor
drugactivation.114Invivo,SLCO1B1c.521T>Cgenotypevariantshadhigher
enalaprilAUCsthanthereferencegenotype,115however,theimpactonthe
drug'sefficacyhasnotbeendelineated.Hydrolysisofenalapriltoenalaprilatis
reportedtooccurwithesteraseactivity;however,thespecificenzymesinvolved
inthisreactionareunknown.Humancarboxylesterases(CES1andCES2)have
anontogenicpatternofincreasingexpressionduringchildhood.116Eventhough
CES1andCES2expressionincreaseswithage,considerableinterindividual
variabilityinmRNA,protein,andhydrolyticactivityexistsamongdifferentage
groups.116,117Fullcharacterizationoftheenzymesinvolvedwithenalapril
activationisrequiredtodeterminethatgenesarerelevantforfuture
pharmacogeneticevaluation.
