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IMPACT OF HIE AND THERAPEUTIC HYPOTHERMIA ON NEONATAL
DRUG THERAPY
KELIANAO’MARA,PHARMD,BCPS
NICUCLINICALPHARMACYSPECIALIST
UFHEALTHSHANDS
AUGUST6,2016
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OBJECTIVES
• DefinebasicpharmacokineJc(PK)andpharmacodynamic(PD)principlesinneonates• DescribehowHIEandtherapeuJchypothermiaimpactPKandPDinneonates• ReviewliteraturetodeterminehowtoopJmizepharmacotherapeuJcmanagementininfantswithHIE
andtherapeuJchypothermia
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DRUG THERAPY
• GoalistoadministeragivendrugatagivendosetoachieveadesiredtherapeuJceffectwhileminimizingriskoftoxicity
PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.
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CHALLENGES TO NEONATAL DRUG THERAPY
• GreatvariabilityindrugdisposiJon• MaturaJonaldevelopment
• Diseasestatevariability
• DrugformulaJons• Neonatal-specificformulaJonso_enlacking
• Highlyconcentrated
• Lowinfusionrates
PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.
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CHALLENGES IN NEONATAL DRUG DOSING
• Muchoftheavailabledataforneonataldosingextrapolatedfromolderchildrenandadults• GestaJonalageandweightaremostcommonvariablesusedtodeterminedoses
• Non-linearrelaJonshipbetweendrugmetabolismandweight
• Bodysurfacearea(BSA)hasbeensuggestedasanalternaJvebuthasnotbeenshowntoincreaseaccuracyorsafety
PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.
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THERAPEUTIC DRUG MONITORING (TDM)
• PowerfultoolforimprovingoutcomesassociatedwithmedicaJonuse• Cancontributetotailoreddrugprescribing• Individualizeddosingtomaximizebenefitswhileminimizingtoxicity• Supportsclinicaldecisionmaking
PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.
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CRITERIA FOR TDM
• WeakcorrelaJonbetweendoseadministeredandconcentraJonreached• Wideinter-paJentvariabilityinconcentraJonwithagivendose• NarrowtherapeuJcrange
• Under/over-exposureresultsinpooreroutcomeormoretoxicity
• AnalyJcaltechniquesufficientlyspecific,precise,accurate,andcosteffecJve
PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.
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REASONS TO NOT USE TDM
• Valueislimitedandtherearemoreconvenientmethodsforassessingeffectsofdosagebasedoneasilyavailableoutcomevariables
• Bloodpressure,analgesia,levelofsedaJon
• BroadconcentraJonrangebeforetoxicity• InabilitytoeffecJvelysample
• TimingofcollecJon,assayvalidity
• AcJvemetabolitescomplicateassessment
PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.
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PHARMACOKINETICS
• Whatthebodydoestothedrug• Describesthemovementofdruginto,through,andoutofthebody
• AbsorpJon
• DistribuJon
• Metabolism
• ExcreJon
ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx
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PHARMACOKINETIC (PK) PARAMETERS
• EliminaJonrate• Half-life• Clearance• VolumeofdistribuJon• PeakconcentraJon• TroughconcentraJon
ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx
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DRUG CONCENTRATION
ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx
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DRUG VOLUME OF DISTRIBUTION
ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx
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PHARMACODYNAMICS (PD)
• Whatthedrugdoestothebody• Receptorbinding,post-receptoreffects,chemicalinteracJons
• WithPK,describesrelaJonshipbetweendrugdoseandeffect• InteracJonscanimpactdrugeffects
• Drug-drug,drug-disease
• GeneJcmutaJonscanchangebindingaffinity,alterbindingproteins,decreasereceptorsensiJvity
ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx
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RELATIONSHIP BETWEEN PK-PD
Drug
PaJentBacteriaInfection
Host Defense
Schentag et al. Pharmacokinetics 3rd Edition. P16-25.
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“PHARMACOPHYSIOLOGY”
• TheuseofapaJent’scalculatedpharmacokineJcparameterstounderstandunderlyingphysiologyordiseaseseverity
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THERMOPHARMACOLOGY
• StudyoftheinfluencehypothermiaonpharmacokineJcparameters• DistribuJon,metabolism,eliminaJon,andeffectofdrugs
• AvoidtoxicityorineffecJvemedicaJontherapy
• InvesJgaJonofbodytemperatureondrugdisposiJon,bodytemperatureeffectondrugeffects,anddrugeffectsupontemperaturehomeostasis
VandenBroekMPHetalClinPharmacokinet2012
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PHYSIOLOGIC EFFECTS OF HIE/HYPOTHERMIA
• Cardiovascular• Hemodynamic• Neurologic• Respiratory• Metabolic/endocrine
• Renal• Fluids/electrolytes• GastrointesJnal• Hematologic• Immunologic
ZanelliSetal.JPerinatol2011
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CARDIOVASCULAR
• Decreasedheartrate• 14to45bpmduringcooling,returnstonormalwithrewarming
• Increasedsystemicvascularresistance• VasoconstricJontoconserveheat,releaseofcatecholaminesandcorJsol
• UnsedatedpaJents
• Decreasedcardiacoutput(CO)• 7%forevery1oCdropincoretemperature• COat33oC67%followingrewarmingto37oC
• Nohypotension-decreaseinCOmatcheddecreaseinoxygenconsumpJon
• Decreasedintravascularvolume
ZanelliSetal.JPerinatol2011
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METABOLIC/ENDOCRINE
• Decreasedmetabolicrate• 5-7%lowermetabolicrateforevery1oCdecreaseincoretemperature
• DecreasedglucoseuJlizaJon• Decreasedinsulinrelease/sensiJvity
• Hyperglycemiaassociatedwithworseneurologicoutcomes
• IncreasedcatecholamineandcorJsolrelease• StressresponseinunsedatedpaJentscanleadtoshivering,increasedmetabolicrate
ZanelliSetal.JPerinatol2011
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RENAL
• DecreasedperfusionandGFR• ImpairedsaltandwaterreabsorpJon• DysregulaJonofdiuresis
• DecreasedurineoutputsecondarytovasoconstricJon
• Increasedurineoutputsecondarytocold-induceddiuresis
ZanelliSetal.JPerinatol2011
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FLUIDS AND ELECTROLYTES
• Impairedpotassiumhomeostasis• Decreased-cellularuptake
• Increased-rewarming
• Decreasedcalcium,magnesium,phosphorous
ZanelliSetal.JPerinatol2011
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GASTROINTESTINAL
• DecreasedintesJnalbloodflow• IntesJnalperfusionmayhavebeenimpaired
• NodifferencesinrateofnecroJzingenterocoliJswhenneonatesfedlow-volumenon-nutriJveenteralfeedings
• Compromisedliverperfusion• Elevatedserumtransaminaselevels
• HypothermiamaybeprotecJve
ZanelliSetal.JPerinatol2011
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PHARMACOKINETIC CONSIDERATIONS
• CytochromeP450funcJonalteredduringhypothermia• ChangesinbindingpocketconformaJon,reducedsubstrateaffinity,slowedrateofredoxreacJons
• Reduceddrugclearance,longerhalf-life
• DecreasedUDPGTacJvity• HemodynamicadaptaJontotemperature
• PeripheralvasoconstricJonshunJngbloodawayfrommuscle,skin,fat
• SmallervolumeofdistribuJon
• Reducedcardiacoutput,increasedvascularresistancereducebloodflowtokidneysandliver
ZanelliSetal.JPerinatol2011
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EFFECT OF REWARMING ON PK
• DrugswithlargevolumeofdistribuJongivenbeforestartofhypothermiacanbesequesteredinperipheralJssues
• UndergorecirculaJonuponrewarming
• HigherserumconcentraJonsthanexpected,greaterriskoftoxicity
• Prolongedhalf-lifewhilecoolingcanundergoincreasedclearanceasenzymaJcacJvityreturnstobaseline
• Sub-therapeuJcserumconcentraJons
ZanelliSetal.JPerinatol2011
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MORPHINE
• CommonlyusedtoprovideanalgesiaandsedaJonduringtherapeuJchypothermia• RequiresmetabolismviaUDPGT2B7toacJvemetabolitemorphine-6-glucuronide(M6G)
• MaturaJondelayedinnormalneonates(
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MORPHINE CLEARANCE IN NEONATES WITH HIE
• ProspecJve,2-centerclinicalPKstudyin20neonateswithmoderatetosevereHIEreceivinghypothermia(33.5oC)
• EligibilityforcoolinginconjuncJonwithCoolCapcriteria
• Exclusioncriteria:needforrenalreplacementtherapy,ECMO,majorcongenitalanomaly
• MorphineconJnuousinfusion• Center1:20mcg/kg/hranddecreasedto10mcg/kg/hr24hoursa_eronsetofhypothermiatreatment
• Center2:40mcg/kgq6h(standarddose50-100mcg/kgq4hinfulltermneonateswithoutHIE)
• Dosesadjustedbasedonclinicalneed,asneeded50-100mcg/kgbolusesforpain/discomfort/shivering
Frymoyeretal.JClinPharmacol2016
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MORPHINE CLEARANCE IN NEONATES WITH HIE
• 2samplingperiodsduringstudy• 1st:12to48hoursa_erstartofhypothermia
• 2nd:48to72hoursa_erstartofhypothermia
• Morphine,M3G,M6Glevelsevaluated• Bodyweight
• RenalfuncJon
• LiverfuncJon
Frymoyeretal.JClinPharmacol2016
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MORPHINE CLEARANCE IN NEONATES WITH HIE
• SignificantimpactonconcentraJons• BirthweightinverselyproporJonalrelaJonship
• SerumcreaJnine
• Noassociatedimpact• GestaJonalage
• ALT
Frymoyeretal.JClinPharmacol2016
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MORPHINE CLEARANCE IN NEONATES WITH HIE
Frymoyeretal.JClinPharmacol2016
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MORPHINE CLEARANCE IN NEONATES WITH HIE
Frymoyeretal.JClinPharmacol2016
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MORPHINE SUMMARY
• PKeffects:• Decreasedclearance
• IncreasedserumconcentraJons
• AcJon:• ConsiderstarJnglowerdose
• Birthweight,SCr
• ConservaJvedoseJtraJon
ZanelliSetal.JPerinatol2011
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GENTAMICIN IN NEONATES WITH HIE
• FrequentlyusedforpresumpJveinfecJon/sepsis• Standarddosesfornon-HIEterminfantsfrequentlyresultsinsupra-therapeuJctroughconcentraJons
• Normothermic:44%
• Hypothermic:36%
• Toxicity:renal,oJc
Frymoyeretal.JPerinatol2013
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GENTAMICIN IN NEONATES WITH HIE
• RetrospecJvechartreviewofneonateswithHIEundergoingtherapeuJchypothermiawhoreceivedgentamicin
• EvaluaJonofimplementaJonofdosingintervalchange• Dosing:5mg/kgq24horq36h
• Coolingcriteria/protocolsamebetweentreatmentperiods• Gentamicinmonitoring:
• Q24h:trougha_er2ndor3rddose
• 36h:peakandtorugh
Frymoyeretal.JPerinatol2013
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GENTAMICIN IN NEONATES WITH HIE
Frymoyeretal.JPerinatol2013
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GENTAMICIN IN NEONATES WITH HIE
Frymoyeretal.JPerinatol2013
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GENTAMICIN SUMMARY
• PKeffects:• DecreasedclearancewithrenaldysfuncJon
• IncreasedserumconcentraJons(troughs)
• AcJon:• Lowerdosesversuslongerinterval
ZanelliSetal.JPerinatol2011
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PHENOBARBITAL IN NEONATES WITH HIE
• HIEismostcommoncauseofseizuresintermnewborns• Phenobarbitalo_enfirst-lineanJconvulsantfortreatment
VandenBroekMPHetalClinPharmacokinet2012
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THERMOPHARMACOLOGICAL APPROACH TO PHENOBARBITAL IN NEWBORNS WITH HYPOTHERMIA • Neonates>36weeksgestaJonwithperinatalasphyxiaundergoingmoderatehypothermiawithin6
hoursofbirthandconJnuedx72hr
• DataobtainedfromprospecJveSHIVERstudy(10DutchLevelIIINICUs)• Phenobarbital20mg/kgdividedinto1-2dosesover20minperdoseifseizuresoccurredorwere
suspectedduringhypothermicphase
• MaintenancedosesnotiniJatedsincetherapeuJcconcentraJonsexpectedtosustainforseveraldaysduetolonghalf-life
• SubsequentdosesonlyadministereduponsuspectedinefficacybasedonclinicalsymptomsoraEEGrecordings
• Second-line:midazolamorlidocaine
VandenBroekMPHetalClinPharmacokinet2012
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THERMOPHARMACOLOGICAL APPROACH TO PHENOBARBITAL IN NEWBORNS WITH HYPOTHERMIA
VandenBroekMPHetalClinPharmacokinet2012
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THERMOPHARMACOLOGICAL APPROACH TO PHENOBARBITAL IN NEWBORNS WITH HYPOTHERMIA
• Overallresponseratetophenobarbital66%• Noclinicalrelevanteffectofmoderatehypothermiaonphenobarbital
• Clearanceisapproximately50%lowerinneonateswithHIE
• AdministraJonofphenobarbitalseemstoreducetransiJonratefromconJnuousnormalvoltagetodisconJnuousnormalvoltageaEEGbackgroundlevelinhypothermicasphyxiatednewborns
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PHENOBARBITAL SUMMARY
• PKeffects:• DecreasedhepaJcmetabolism!reduceddrugclearance
• AcJon:• MonitorserumconcentraJons
• Maintenancedosesmaynotneedtobestartedforseveraldays
ZanelliSetal.JPerinatol2011
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FENTANYL
• PKeffects-sequestraJonofdruginperiphery• DecreasedvolumeofdistribuJon
• Decreasedclearance
• IncreasedserumconcentraJons
• AcJon:• ConsiderstarJnglowerdose
• ConservaJvedoseJtraJon
• Monitoringforincreasedresponseduringrewarming
ZanelliSetal.JPerinatol2011
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MIDAZOLAM
• PKeffects:• Decreasedclearance
• IncreasedvolumeofdistribuJon
• IncreasedserumconcentraJons
• AcJon:• Startlowerdose
• ConservaJveJtraJon
• Monitorforwithdrawalorseizuresduringrewarming
ZanelliSetal.JPerinatol2011
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VECURONIUM
• PKeffects:• Decreasedclearance
• AcJon:• UselowesteffecJvedose
• ConsiderperiodicdisconJnuaJontoallowformovement
ZanelliSetal.JPerinatol2011
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PHENYTOIN
• PKeffects:• Decreasedclearance
• IncreasedserumconcentraJons
• AcJon:• LowerstarJngdose
• Doseadjustmentsmaybeneededduringrewarming
ZanelliSetal.JPerinatol2011
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TOPIRAMATE
• PKeffects:• LongerJmetomaxconcentraJons
• Decreasedclearance
• IncreasedserumconcentraJon
• AcJon:• Oncedailydosing
ZanelliSetal.JPerinatol2011
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CONCLUSIONS
• PharmacokineJcsmaybealteredbythepresenceofHIEandtherapeuJchypothermia• Effectmayyieldclinicallysignificantriskoftoxicityorunder-treatment
• Effectmaybeclinicallyirrelevant
• Sincehypothermiaisnowstandardofcareformoderate-severeHIE,hardtodetermineifPKchangesarefromHIEorhypothermia
• IndividualizedpharmacotherapeuJcplansmaybenecessarytoopJmizeresponseandminimizeriskoftoxicity
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QUESTIONS