Andersons pediatric cardiology 2106
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Dose-Exposure-ResponseRelationship
Pediatricpharmacotherapy,similartoadultpharmacotherapy,isdependentona
clearunderstandingofthedose-exposure-responserelationshipofthe
administereddrugtopredictaresponseforagivendose.Providersmust
recognizethatmanydrug(e.g.,formulation,proteinbindingaffinitycoefficient,
physicochemicalproperties)andpatientfactors(e.g.,age,Tannerstaging,
cardiacphysiology,altereddrugmetabolismortransport)contributetothe
systemicexposure(e.g.,dose-exposurerelationship)ofadrugfortheindividual
childandtherebyinfluencesdrugresponse.Forexample,poorresponderstoa
particulardrugmaynothavegeneticvariationofthedrugtargetaffecting
responsebutalternativelyhaveinsufficientexposureatthedrugtargetto
generateanadequateresponse.Fig.79.2illustratesthecomplexityinvolvedin
precision-guidedtherapy,outliningeachlevelofthedrugdispositionpathway,
absorptionthroughelimination,thatmustbeconsideredasapotentialsourcefor
variabledrugexposure(e.g.,dose-exposurerelationship).
FIG.79.2 Dose-exposure-responserelationship.Followingdrug
administrationbytheoralroute,absorptionoccurspassivelyorthrougha
transport-mediatedprocessintheenterocyte.Drugmetabolizingenzymes
(DMEs)attheleveloftheenterocytecancontributeforselectivesubstrates
tothepresystemicclearanceoforallyadministereddrugs.Following
absorption,drugsenteringtheportalvenoussystemcanundergoafirstpasseffectatthelevelofthehepatocyte,eitherpassivelyorthrough
transport-mediateduptake.DMEscanactivateordeactivateselective
drugsandconjugatethemforelimination.Drugsenteringsystemic
circulationcanbeclearedbyrenaltubulecells.Alternatively,drugs
administeredintravenouslyentersystemiccirculationdirectly.Collectively,
onemustfactorallthestepsofdrugdisposition(e.g.,dose-exposure
relationship)firstpriortoimplementingpharmacogenomicstestingatthe
responselevel.
Evenwhenthedose-exposurerelationshiphasbeenoptimized,variabledrug
responsecanbeaproductoftwomechanisms:(1)abnormaldrug-target
interaction(e.g.,drugtargetgeneticvariation)or(2)abnormaldrug-target
signalingfollowinganormaldrug-targetinteraction.Asalludedtoearlier,before
developmentandgeneticvariationatthedrugtargetsandassociatedsignaling
pathways(e.g.,responsepathways)areconsideredinclinicalpracticefor
precision-guidedtherapy,itiscrucialtoinitiallydetermineifgeneticvariation
contributingtoalteredsystemicexposureisthesourceofvariableresponse,
meaningthattheperceivedresponseisnotsecondarytopoororexcessivedrug
exposureatthedrugtarget.
Arecentreviewofdevelopmentalpharmacologydescribedtheknown
developmentaspectsofdrugdispositionthatshouldbeconsideredfor
pediatrics.5Inpediatricpharmacotherapy,extrapolationofadultexperiencesis
complicatedbyage-associateddifferencesinthepharmacokineticsofseveral
pharmacologicagentsusedclinicallyinchildren.7Thereforedevelopment(e.g.,
ontogenyofdrugmetabolizingenzymesortransporters)isanotherconsideration
thatmustbeaddedwhencharacterizingthedose-exposurerelationshipina
child.Untilweunderstandandfullycharacterizethepediatricdrugdisposition
pathways,itwillnotbefeasibletocontroltheexposureatthedrugtarget
followingagivendoseinamannerthatwillimproveclinicaltrialoutcomes.
Genotype-stratifiedpharmacokineticstudiesperformedseparatelyina
pediatriccohort,describedinthesectionPracticalApplications:Statins,allow
forfullcharacterizationoftheanticipatedextremesofthedose-exposure
relationship.Subsequently,theseinitialdataassistinthedevelopmentof
pharmacogenomicinvestigationsutilizingindividualizeddosingtoachievea
targetexposureandreduceinterindividualvariability.4Collectively,
pharmacogenomicscanbeutilizedtoenhancepediatricdosingguidelinesand
provideprecision-guidedcare.
Intheabsenceofmorecomprehensivepediatricdata,however,asystematic
approachhasbeendevelopedtogathermoreinformationaboutcertaindrugsand
identifyknowledgegapstomoreaccuratelyinformprospectivepediatrictrials
andclinicaldecisionmaking.3,8Thefundamentalquestionsoutlinedinthese
referencedmanuscriptsareasfollows.(1)Whatgeneproductsarequantitatively
importantinthedisposition(absorption,distribution,metabolism,andexcretion)
ofthedrug?(2)Whatknownallelicvariantsinthegenesofinterestare
associatedwithfunctionalconsequenceinvivo?(3)Whatisthedevelopmental
profile(ontogeny)ofthekeypathwaysinvolvedinthedrug'sdisposition?
