IMPACT OF HIE AND THERAPEUTIC HYPOTHERMIA ON NEONATAL

DRUG THERAPY

KELIANAO’MARA,PHARMD,BCPS

NICUCLINICALPHARMACYSPECIALIST

UFHEALTHSHANDS

AUGUST6,2016

OBJECTIVES

•  DefinebasicpharmacokineJc(PK)andpharmacodynamic(PD)principlesinneonates•  DescribehowHIEandtherapeuJchypothermiaimpactPKandPDinneonates•  ReviewliteraturetodeterminehowtoopJmizepharmacotherapeuJcmanagementininfantswithHIE

andtherapeuJchypothermia

DRUG THERAPY

•  GoalistoadministeragivendrugatagivendosetoachieveadesiredtherapeuJceffectwhileminimizingriskoftoxicity

PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.

CHALLENGES TO NEONATAL DRUG THERAPY

•  GreatvariabilityindrugdisposiJon•  MaturaJonaldevelopment

•  Diseasestatevariability

•  DrugformulaJons•  Neonatal-specificformulaJonso_enlacking

•  Highlyconcentrated

•  Lowinfusionrates

PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.

CHALLENGES IN NEONATAL DRUG DOSING

•  Muchoftheavailabledataforneonataldosingextrapolatedfromolderchildrenandadults•  GestaJonalageandweightaremostcommonvariablesusedtodeterminedoses

•  Non-linearrelaJonshipbetweendrugmetabolismandweight

•  Bodysurfacearea(BSA)hasbeensuggestedasanalternaJvebuthasnotbeenshowntoincreaseaccuracyorsafety

PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.

THERAPEUTIC DRUG MONITORING (TDM)

•  PowerfultoolforimprovingoutcomesassociatedwithmedicaJonuse•  Cancontributetotailoreddrugprescribing•  Individualizeddosingtomaximizebenefitswhileminimizingtoxicity•  Supportsclinicaldecisionmaking

PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.

CRITERIA FOR TDM

•  WeakcorrelaJonbetweendoseadministeredandconcentraJonreached•  Wideinter-paJentvariabilityinconcentraJonwithagivendose•  NarrowtherapeuJcrange

•  Under/over-exposureresultsinpooreroutcomeormoretoxicity

•  AnalyJcaltechniquesufficientlyspecific,precise,accurate,andcosteffecJve

PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.

REASONS TO NOT USE TDM

•  Valueislimitedandtherearemoreconvenientmethodsforassessingeffectsofdosagebasedoneasilyavailableoutcomevariables

•  Bloodpressure,analgesia,levelofsedaJon

•  BroadconcentraJonrangebeforetoxicity•  InabilitytoeffecJvelysample

•  TimingofcollecJon,assayvalidity

•  AcJvemetabolitescomplicateassessment

PauwelsS,AllegaertK.ArchDisChild2016;0:1–5.

PHARMACOKINETICS

•  Whatthebodydoestothedrug•  Describesthemovementofdruginto,through,andoutofthebody

•  AbsorpJon

•  DistribuJon

•  Metabolism

•  ExcreJon

ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx

PHARMACOKINETIC (PK) PARAMETERS

•  EliminaJonrate•  Half-life•  Clearance•  VolumeofdistribuJon•  PeakconcentraJon•  TroughconcentraJon

ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx

DRUG CONCENTRATION

ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx

DRUG VOLUME OF DISTRIBUTION

ASHPChapter.hep://www.ashp.org/doclibrary/bookstore/p2418-chapter1.aspx

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

RELATIONSHIP BETWEEN PK-PD

Drug

PaJentBacteriaInfection

Host Defense

Schentag et al. Pharmacokinetics 3rd Edition. P16-25.

“PHARMACOPHYSIOLOGY”

•  TheuseofapaJent’scalculatedpharmacokineJcparameterstounderstandunderlyingphysiologyordiseaseseverity

THERMOPHARMACOLOGY

•  StudyoftheinfluencehypothermiaonpharmacokineJcparameters•  DistribuJon,metabolism,eliminaJon,andeffectofdrugs

•  AvoidtoxicityorineffecJvemedicaJontherapy

•  InvesJgaJonofbodytemperatureondrugdisposiJon,bodytemperatureeffectondrugeffects,anddrugeffectsupontemperaturehomeostasis

VandenBroekMPHetalClinPharmacokinet2012

PHYSIOLOGIC EFFECTS OF HIE/HYPOTHERMIA

•  Cardiovascular•  Hemodynamic•  Neurologic•  Respiratory•  Metabolic/endocrine

•  Renal•  Fluids/electrolytes•  GastrointesJnal•  Hematologic•  Immunologic

ZanelliSetal.JPerinatol2011

CARDIOVASCULAR

•  Decreasedheartrate•  14to45bpmduringcooling,returnstonormalwithrewarming

•  Increasedsystemicvascularresistance•  VasoconstricJontoconserveheat,releaseofcatecholaminesandcorJsol

•  UnsedatedpaJents

•  Decreasedcardiacoutput(CO)•  7%forevery1oCdropincoretemperature•  COat33oC67%followingrewarmingto37oC

•  Nohypotension-decreaseinCOmatcheddecreaseinoxygenconsumpJon

•  Decreasedintravascularvolume

ZanelliSetal.JPerinatol2011

METABOLIC/ENDOCRINE

•  Decreasedmetabolicrate•  5-7%lowermetabolicrateforevery1oCdecreaseincoretemperature

•  DecreasedglucoseuJlizaJon•  Decreasedinsulinrelease/sensiJvity

•  Hyperglycemiaassociatedwithworseneurologicoutcomes

•  IncreasedcatecholamineandcorJsolrelease•  StressresponseinunsedatedpaJentscanleadtoshivering,increasedmetabolicrate

ZanelliSetal.JPerinatol2011

RENAL

•  DecreasedperfusionandGFR•  ImpairedsaltandwaterreabsorpJon•  DysregulaJonofdiuresis

•  DecreasedurineoutputsecondarytovasoconstricJon

•  Increasedurineoutputsecondarytocold-induceddiuresis

ZanelliSetal.JPerinatol2011

FLUIDS AND ELECTROLYTES

•  Impairedpotassiumhomeostasis•  Decreased-cellularuptake

•  Increased-rewarming

•  Decreasedcalcium,magnesium,phosphorous

ZanelliSetal.JPerinatol2011

GASTROINTESTINAL

•  DecreasedintesJnalbloodflow•  IntesJnalperfusionmayhavebeenimpaired

•  NodifferencesinrateofnecroJzingenterocoliJswhenneonatesfedlow-volumenon-nutriJveenteralfeedings

•  Compromisedliverperfusion•  Elevatedserumtransaminaselevels

•  HypothermiamaybeprotecJve

ZanelliSetal.JPerinatol2011

PHARMACOKINETIC CONSIDERATIONS

•  CytochromeP450funcJonalteredduringhypothermia•  ChangesinbindingpocketconformaJon,reducedsubstrateaffinity,slowedrateofredoxreacJons

•  Reduceddrugclearance,longerhalf-life

•  DecreasedUDPGTacJvity•  HemodynamicadaptaJontotemperature

•  PeripheralvasoconstricJonshunJngbloodawayfrommuscle,skin,fat

•  SmallervolumeofdistribuJon

•  Reducedcardiacoutput,increasedvascularresistancereducebloodflowtokidneysandliver

ZanelliSetal.JPerinatol2011

EFFECT OF REWARMING ON PK

•  DrugswithlargevolumeofdistribuJongivenbeforestartofhypothermiacanbesequesteredinperipheralJssues

•  UndergorecirculaJonuponrewarming

•  HigherserumconcentraJonsthanexpected,greaterriskoftoxicity

•  Prolongedhalf-lifewhilecoolingcanundergoincreasedclearanceasenzymaJcacJvityreturnstobaseline

•  Sub-therapeuJcserumconcentraJons

ZanelliSetal.JPerinatol2011

MORPHINE

•  CommonlyusedtoprovideanalgesiaandsedaJonduringtherapeuJchypothermia•  RequiresmetabolismviaUDPGT2B7toacJvemetabolitemorphine-6-glucuronide(M6G)

•  MaturaJondelayedinnormalneonates(

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

MORPHINE CLEARANCE IN NEONATES WITH HIE

•  2samplingperiodsduringstudy•  1st:12to48hoursa_erstartofhypothermia

•  2nd:48to72hoursa_erstartofhypothermia

•  Morphine,M3G,M6Glevelsevaluated•  Bodyweight

•  RenalfuncJon

•  LiverfuncJon

Frymoyeretal.JClinPharmacol2016

MORPHINE CLEARANCE IN NEONATES WITH HIE

•  SignificantimpactonconcentraJons•  BirthweightinverselyproporJonalrelaJonship

•  SerumcreaJnine

•  Noassociatedimpact•  GestaJonalage

•  ALT

Frymoyeretal.JClinPharmacol2016

MORPHINE CLEARANCE IN NEONATES WITH HIE

Frymoyeretal.JClinPharmacol2016

MORPHINE CLEARANCE IN NEONATES WITH HIE

Frymoyeretal.JClinPharmacol2016

MORPHINE SUMMARY

•  PKeffects:•  Decreasedclearance

•  IncreasedserumconcentraJons

•  AcJon:•  ConsiderstarJnglowerdose

•  Birthweight,SCr

•  ConservaJvedoseJtraJon

ZanelliSetal.JPerinatol2011

GENTAMICIN IN NEONATES WITH HIE

•  FrequentlyusedforpresumpJveinfecJon/sepsis•  Standarddosesfornon-HIEterminfantsfrequentlyresultsinsupra-therapeuJctroughconcentraJons

•  Normothermic:44%

•  Hypothermic:36%

•  Toxicity:renal,oJc

Frymoyeretal.JPerinatol2013

GENTAMICIN IN NEONATES WITH HIE

•  RetrospecJvechartreviewofneonateswithHIEundergoingtherapeuJchypothermiawhoreceivedgentamicin

•  EvaluaJonofimplementaJonofdosingintervalchange•  Dosing:5mg/kgq24horq36h

•  Coolingcriteria/protocolsamebetweentreatmentperiods•  Gentamicinmonitoring:

•  Q24h:trougha_er2ndor3rddose

•  36h:peakandtorugh

Frymoyeretal.JPerinatol2013

GENTAMICIN IN NEONATES WITH HIE

Frymoyeretal.JPerinatol2013

GENTAMICIN IN NEONATES WITH HIE

Frymoyeretal.JPerinatol2013

GENTAMICIN SUMMARY

•  PKeffects:•  DecreasedclearancewithrenaldysfuncJon

•  IncreasedserumconcentraJons(troughs)

•  AcJon:•  Lowerdosesversuslongerinterval

ZanelliSetal.JPerinatol2011

PHENOBARBITAL IN NEONATES WITH HIE

•  HIEismostcommoncauseofseizuresintermnewborns•  Phenobarbitalo_enfirst-lineanJconvulsantfortreatment

VandenBroekMPHetalClinPharmacokinet2012

THERMOPHARMACOLOGICAL APPROACH TO PHENOBARBITAL IN NEWBORNS WITH HYPOTHERMIA •  Neonates>36weeksgestaJonwithperinatalasphyxiaundergoingmoderatehypothermiawithin6

hoursofbirthandconJnuedx72hr

•  DataobtainedfromprospecJveSHIVERstudy(10DutchLevelIIINICUs)•  Phenobarbital20mg/kgdividedinto1-2dosesover20minperdoseifseizuresoccurredorwere

suspectedduringhypothermicphase

•  MaintenancedosesnotiniJatedsincetherapeuJcconcentraJonsexpectedtosustainforseveraldaysduetolonghalf-life

•  SubsequentdosesonlyadministereduponsuspectedinefficacybasedonclinicalsymptomsoraEEGrecordings

•  Second-line:midazolamorlidocaine

VandenBroekMPHetalClinPharmacokinet2012

THERMOPHARMACOLOGICAL APPROACH TO PHENOBARBITAL IN NEWBORNS WITH HYPOTHERMIA

VandenBroekMPHetalClinPharmacokinet2012

THERMOPHARMACOLOGICAL APPROACH TO PHENOBARBITAL IN NEWBORNS WITH HYPOTHERMIA

•  Overallresponseratetophenobarbital66%•  Noclinicalrelevanteffectofmoderatehypothermiaonphenobarbital

•  Clearanceisapproximately50%lowerinneonateswithHIE

•  AdministraJonofphenobarbitalseemstoreducetransiJonratefromconJnuousnormalvoltagetodisconJnuousnormalvoltageaEEGbackgroundlevelinhypothermicasphyxiatednewborns

PHENOBARBITAL SUMMARY

•  PKeffects:•  DecreasedhepaJcmetabolism!reduceddrugclearance

•  AcJon:•  MonitorserumconcentraJons

•  Maintenancedosesmaynotneedtobestartedforseveraldays

ZanelliSetal.JPerinatol2011

FENTANYL

•  PKeffects-sequestraJonofdruginperiphery•  DecreasedvolumeofdistribuJon

•  Decreasedclearance

•  IncreasedserumconcentraJons

•  AcJon:•  ConsiderstarJnglowerdose

•  ConservaJvedoseJtraJon

•  Monitoringforincreasedresponseduringrewarming

ZanelliSetal.JPerinatol2011

MIDAZOLAM

•  PKeffects:•  Decreasedclearance

•  IncreasedvolumeofdistribuJon

•  IncreasedserumconcentraJons

•  AcJon:•  Startlowerdose

•  ConservaJveJtraJon

•  Monitorforwithdrawalorseizuresduringrewarming

ZanelliSetal.JPerinatol2011

VECURONIUM

•  PKeffects:•  Decreasedclearance

•  AcJon:•  UselowesteffecJvedose

•  ConsiderperiodicdisconJnuaJontoallowformovement

ZanelliSetal.JPerinatol2011

PHENYTOIN

•  PKeffects:•  Decreasedclearance

•  IncreasedserumconcentraJons

•  AcJon:•  LowerstarJngdose

•  Doseadjustmentsmaybeneededduringrewarming

ZanelliSetal.JPerinatol2011

TOPIRAMATE

•  PKeffects:•  LongerJmetomaxconcentraJons

•  Decreasedclearance

•  IncreasedserumconcentraJon

•  AcJon:•  Oncedailydosing

ZanelliSetal.JPerinatol2011

CONCLUSIONS

•  PharmacokineJcsmaybealteredbythepresenceofHIEandtherapeuJchypothermia•  Effectmayyieldclinicallysignificantriskoftoxicityorunder-treatment

•  Effectmaybeclinicallyirrelevant

•  Sincehypothermiaisnowstandardofcareformoderate-severeHIE,hardtodetermineifPKchangesarefromHIEorhypothermia

•  IndividualizedpharmacotherapeuJcplansmaybenecessarytoopJmizeresponseandminimizeriskoftoxicity

QUESTIONS