Pharmacology of enalapril in children: a review

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Pleasecitethisarticleinpressas:Smeets,N.J.L.etal.Pharmacologyofenalaprilinchildren:areview,DrugDiscovToday(2020),https://doi.org/10.1016/j.drudis.2020.08.005

DrugDiscoveryTodayVolume00,Number00August2020 REVIEWS

Pharmacology

of

enalapril

in

children:

a

review

Nori

J.L.

Smeets

1

,

Michiel

F. Schreuder

2

,

Michiel

Dalinghaus

3

,

Christoph

Male

4

,

Florian

B. Lagler

5

,

Jennifer

Walsh

6

,

Stephanie

Laer

7

and

Saskia

N. de

Wildt

1,8

1_Department_of_Pharmacology_and_Toxicology,_Radboud_Institute_of_Health_Sciences,_Radboudumc,_Nijmegen, theNetherlands

2_Department_of_Pediatric_Nephrology,_Radboud_Institute_of_Molecular_Sciences,_Radboudumc_Amalia_Children_’s Hospital,Nijmegen,theNetherlands

3_Department_of_Pediatric_Cardiology,_Erasmus_MC_–_Sophia,_Rotterdam,_the_Netherlands

4_Department_of_Paediatrics_and_Adolescent_Medicine,_Medical_University_of_Vienna,_Vienna,_Austria 5_Paracelsus_Medizinische_{Privatuniversität,}_Salzburg,_Austria

6_Ethicare_GmbH,_Haltern_am_See,_Germany

7_Institute_of_Clinical_Pharmacy_and_{Pharmacotherapy,}_{Heinrich-Heine-University}_Düsseldorf,_Düsseldorf,_Germany 8_Department_of_Intensive_Care_and_Pediatric_Surgery,_Erasmus_MC_–_Sophia_Children_’s_Hospital,_Rotterdam,_the Netherlands

Enalapril

is

an

angiotensin-converting

enzyme

(ACE)

inhibitor

that

is

used

for

the

treatment

of

(paediatric)

hypertension,

heart

failure

and

chronic

kidney

diseases.

Because

its

disposition,

efficacy

and

safety

differs

across

the

paediatric

continuum,

data

from

adults

cannot

be

automatically

extrapolated

to

children.

This

review

highlights

paediatric

enalapril

pharmacokinetic

data

and

demonstrates

that

these

are

inadequate

to

support

with

certainty

an

age-related

effect

on

enalapril/enalaprilat

pharmacokinetics.

In

addition,

our

review

shows

that

evidence

to

support

effective

and

safe

prescribing

of

enalapril

in

children

is

limited,

especially

in

young

children

and

heart

failure

patients;

studies

in

these

groups

are

either

absent

or

show

conflicting

results.

We

provide

explanations

for

observed

differences

between

age

groups

and

indications,

and

describe

areas

for

future

research.

Introduction

Enalapril was the second angiotensin-converting enzyme (ACE) inhibitor to become widely availablefor therapeuticuse aftercaptopril,the first registered oralACEinhibitor. Enalapril is an ethyl ester pro-drug, and its pharmacological effects are mediated by its activemetabolite,enalaprilat(alsoknown asMK422).Themain effectofenalaprilatisthe inhibitionofACE,akeycomponentinthereninangiotensinaldosteronesystem(RAAS).This leadstoadecreaseintheformationofangiotensinIIandtherebytoperipheralvasodilation.

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NoriSmeetsobtainedher

medicaldegreefrom

RadboudUniversityin

Nijmegen,theNetherlands.

Currently,sheisaMDPhD

candidateandclinical

pharmacologistintrainingat

thedepartmentof

Pharmacologyand

Toxicology,RadboudUniversity,underthe

supervisionofSaskiadeWildtandMichielSchreuder.

Herresearchfocusesontheontogenyofrenal

functioninrelationtodrugdosing,withaspecialfocus

oncriticallyillneonatesandchildren.

MichielSchreuderisan

associateprofessorof

paediatricnephrologyatthe

RadboudumcAmalia

Children’sHospitalin

Hecombinesclinicalwork

withresearchtooptimize

treatmentforchildrenwith

renaldisordersthroughbasicandtranslationalstudies

andclinicaltrials.Hismainresearchtopicsarenormal

andabnormalkidneydevelopment,andnephrotic

syndrome.Theinteractionbetweenthekidneyand

drugsisoneofhisinterests,rangingfromtheeffectof

drugsonkidneydevelopmenttodosing

recommendationsinkidneyfailure.

SaskiadeWildtisafull

professorofclinical

pharmacologyinthe

departmentofPharmacology

andToxicologyatRadboud

UniversityMedicalCenterin

Sheisacertifiedclinical

pharmacologistandcombines

researchwithclinicalcareinthePaediatricIntensive

Caredepartment.Sheaimstobetterunderstandthe

impactofage,diseaseandgeneticsondrugdisposition

andtoindividualizedrugdosinginchildren,witha

focusonpainandsedation,andacutekidneyinjury.

Furthermore,deWildtisdirectoroftheDutch

KnowledgeCenterforPharmacotherapyinChildren,

andassuchisresponsiblefortheDutchPaediatric

DrugHandbookanditsinternationalaffiliates.

Correspondingauthor:deWildt,S.N. (Saskia.deWildt@radboudumc.nl)

1359-6446/ã2020TheAuthor(s).PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

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Thisisfollowedbyadiminishedsecretionofaldosterone, caus-ing less sodium and fluid retention. These two mechanisms causeadecreaseinbloodpressure(BP),andadecreasedpreload andafterloadoftheheart[1].Inadditiontoits stimulatory effectonaldosteronesecretion,angiotensinIIisabletodirectly increasetheactivityoftheepithelialsodiumchannel[2].This leadstomaximumsodium reabsorption,a processthatisalso reduced byACEinhibitors.Inadults,enalaprilis usedforthe treatment of hypertension and heart failure, as well as for reducingproteinuriainchronickidneydisease(CKD).In addi-tiontotheirBPloweringeffect,ACEinhibitorshavearoleinthe treatmentofpatients withheartfailure,becausetheyprevent (further)cardiacremodelling[3].InCKD,thebeneficialeffectof enalaprilismostlytheresultofadecreaseinglomerularpressure duetoa relaxationoftheefferentarterioles[4].

Inchildren,enalaprilisusedforsimilarindications,butinthe European Unionitisonlyauthorisedforuseinchildrenwitha bodyweightover20kg[5].Althoughthislabelindicatesapositive benefit/riskratioofenalaprilonthebasisofanevaluationbythe EuropeanMedicinesAgency,dataonthepharmacokinetics(PK) and pharmacodynamics(PD)ofenalaprilinthispopulation ap-pearscarce.Inchildrenbelowtheweightof20kg,evenlessdata areavailable.Currentdoserecommendationsarebasedon empir-icalevidencecombinedwithdataextrapolatedfromadultstudies, and asa consequence, a disparityin dosagecriteriaremains in paediatricpatients[6].

Theimportanceofpharmacologicaltreatmentinchildrenwith heartfailure,especiallydilatedcardiomyopathies,isemphasised by the lowavailability ofdonor hearts.Owingto this scarcity, mortalitywithinthefirstyearofpresentationremainsextremely high,highlightingtheneedforoptimaltreatmentinchildrento preventorpostponetransplantation[7].

Thisreviewaimstoprovideanoverviewofcurrentknowledge on enalaprilPKand PD characteristicsin childrenand identify current knowledge gaps,as well as to suggest areas for further

study.AdultPKdataareincludedifandwhenrelevantto paediat-ricPKdata.

Pharmacokinetics

Disposition

of

enalapril

Becausetheactivemetaboliteofenalapril,enalaprilat,ispoorly absorbedfromthegastrointestinaltract,enalaprilisadministered asamaleatesalttoimproveitsabsorption[8].Inadults, approxi-mately60–70%ofenalaprilisabsorbedafteroraladministration [8].Dataontheintestinaluptakemechanismshowinconsistent results. It has previously been hypothesised that enalapril is a substratefor the low-affinity H+ peptide transporter 1 (PEPT1), becauseitsstructureresemblesAla-Prodipeptideor Xaa-Ala-Pro tripeptide structures, which are intestinal PEPT1 substrates [9]. Becausethereportedaffinityconstantsweresignificantlydifferent between studies, experiments were repeated [10,11]. Morrison etal.studiedtheinvitrouptakeofenalaprilinbothratintestinal ringsandCaco-2cells(humancellsthatresembletheenterocytes liningthesmallintestine).Theirresultsindicatethatenalaprilis absorbedthroughapassivediffusionprocessanditstransport is non-saturable[10].Inthreedifferentcellexperimentsperformed by Knutter et al., an almost negligible affinity of enalapril for transport by PEPT1and PEPT2 wasfound [11].Therefore,they alsoconcludedthattransportinintestinalcellsisnotmediatedvia thosetransporters.Theypostulate,basedonthelipophilic char-acteristicsofenalapril,thatuptakeoccursviasimplediffusion.On the basis of these two studies, the involvement of a human intestinaltransporterinthe uptakeofenalaprilisconsideredto beunlikely.Whetherthistransportisparacellularortranscellular remainstobeundetermined.

Inhealthy volunteers, enalapril maximumserum concentra-tions(Cmax)ofaround45–49ng/mloccurapproximately1hafter

oralingestionofa10mgtablet[12,13].However,thesevaluesare measuredusing alkalinehydrolysis followed by ACE-inhibition assays.This meansthat allenalapril andenalaprilat levelswere

Enterocyte Hepatocyte Proximal tubule cell

Enalaprilat Enalapril

Enalapril

Passive diffusion Transporter mediated Transporter mediated

Drug Discovery Today

FIGURE1

Transportofenalaprilthroughvariousmembranes.Abbreviations:CES1,carboxylesterase1;MRP2,multidrugresistance-associatedprotein2;MRP4,multidrug resistance-associatedprotein4;OAT3,organicaniontransporter3;OATP1B1,organicaniontransportingpolypeptide1B1;OATP1B3,organicaniontransporting polypeptide1B3. 2 www.drugdiscoverytoday.com Reviews KEYNO TE REVIEW

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measuredusing aradioimmunoassayprocedure inwhich enala-prilatwasdirectlymeasuredbutenalaprillevelswerededucedon the basis ofvalues obtained before and afterhydrolysis. When measured using a more recently developed high-performance liquid chromatography method, enalapril Cmax values were

aroundten timeshigher[14].Also,aslightinaccuracyin deter-miningenalaprilatconcentrationsusingthismethodwas demon-stratedwhencomparedwithnewerassays,suchasenzyme-linked immunosorbent assays [15] or high-performance liquid chromatography–tandemmassspectrometry[16].Inourreview, tocompareadultandpaediatricstudies,weusedthevaluesderived bytheradioimmunoassay.Theoralbioavailabilityofenalaprilwas 61% on the basis of urinary excretion data when intravenous enalaprilatwasusedasareferencestandard[17].Theelimination half-life(T1/2)ofenalaprilis1.6(SD1.5)h[14].

Conversion

to

enalaprilat

Afterabsorptionfromthesmallintestine(Fig.1),uptakeofenalapril inhepatocytesismediatedbytheorganicaniontransporting poly-peptide1B1(OATP1B1)andOATP1B3[18].Approximately60%of enalaprilismetabolisedinthehepatocytetoitsactivemetabolite, enalaprilat,byoneofthemajorhepatichydrolases,carboxylesterase 1(CES1)[13].Byremovingtheethylesterfromenalapriltoform enalaprilat,themoleculebecomesnegativelycharged,andits po-tency to inhibit ACEincreases.Followingits formation, enalaprilat is transportedintothesystemiccirculationbymultidrug resistance-associatedprotein4(MRP4)[19].But,becausehepaticMRP4 expres-sionishighlyvariable[20],theinvolvementofotherbasolateral transporterscannotbeexcluded.Althoughmostenalaprilwillbe eventuallyexcretedrenallyasenalaprilat,untransformedenalapril isexcretedinbilebyMRP2[18]orexcretedbackintothesystemic circulationbyanunknowntransporter.

Peakconcentrationsofenalaprilatareobservedbetween3.5and 4.5hafteringestioninhealthyadultvolunteersandarebetween 54.8 and 57.2ng/mL [14] after a dose of 10mg. These values coincide with maximum inhibition of ACE [12], and over the usualtherapeuticrange,thereisadirectlinearcorrelationbetween the Cmax of enalaprilat and given dose of enalapril [21]. The

observedareaunderthecurve(AUC0–infinity)was255.9–266.9ng

h/ml[14].Theproteinbindingofenalaprilatinthecirculationis reportedtobealittlelessthan50%,anditpenetratesintomost tissues,includingthevascularendotheliumofthelungs[21].In thelung,ACEexistsattheendothelialcellsurface,whereitisshed andhydrolysescirculatingpeptides[22].

Elimination

Theexcretionofenalaprilatispredominantlyrenal;43%ofthe enalapril dose is recovered in urine as enalaprilat and 18% is recoveredasenalapril[13].Thisrenaleliminationofenalaprilat isbiphasic.Theinitialphaseseemstoreflectglomerularfiltration combinedwithtubularsecretion,followedbyalater phasethat reflectstheequilibriumofthedrugfromtissuedistributionsites [23].Theentryofenalaprilatintotheproximaltubularlumenis thought to be transporter-mediated, because the clearance of enalaprilat exceeds that of the glomerular filtrationrate (GFR) marker inulin. This suggests that the elimination is based on glomerularfiltrationaswellasontubularsecretion[24].Because enalaprilatisananionandtheexcretionofanotherACEinhibitor

(quinalaprilat) excretionis decreasedinthe presenceoforganic anions[25],itislikelythatthissecretionismediatedbyanorganic aniontransporter. Thiswasindeed confirmedby Nietal.,who showedthattheuptakeofenalaprilatismediatedbytheorganic aniontransporter3[26].

Reportedclearancesofenalaprilatrangefrom158(SD46)ml/ min[13]to173(SD13)ml/min[27],determinedafter adminis-trationofenalapril.Afteroraladministrationofenalaprilor intra-venous administration of enalaprilat itself in healthy adult volunteers,theeffectivehalf-lifeofenalaprilataftermultipledoses range from 3.5 to 11h [12–14,27,28]. The terminal half-life is muchlongerat35–38h,whichispresumablycausedbybinding ofenalaprilattoACE[28],thusleadingtoslowerelimination.To make steady-state predictions, the effective half-life should be used;theprolongedterminalphasecontributeslittletothe accu-mulationofenalaprilatbecausethisinvolvesredistributionfrom thetissuedistributionsites.

Estimatesofthevolumeofdistribution(Vd)ofenalaprilatare not available in the literature but can be calculated using the formula Vd=T1/2 clearance (CL)/0.693 [29], assuming 100%

conversionofenalapriltoenalaprilat.Thisyieldsvaluesbetween 47and148l(CLderivedfrom[13],T1/2from[12–14,27,28].

Factors

influencing

PK

TherearemanyfactorsthatcaninfluenceenalaprilPK,ofwhich diseaseisamajorone.ThePKofbothenalaprilandenalaprilatis notaltered inpatients withhypertension[30].Inpatients with congestiveheartfailure(CHF),thisislessapparent.TwoPKstudies comparedCHF patientsto healthyvolunteersand hypertensive patients,respectively.Aslowerabsorptionrate wassuggestedin CHF patients,butowingtothe smallsamplesize,nostatistical significancecouldbeshown[31,32].

The absorptionofenalapril tabletsis notinfluencedby food [33,34].Interestingly,whenstudyingtheimpactoffoodonanoral enalaprilsuspension,asignificantlylongerenalaprilatTmax,lower

Cmax and lower AUC 0–infinity for enalaprilat were seen in 48

healthyvolunteersafterintakeofahigh-fatmealcomparedwith fasting[35].Becauseorallyadministereddrugintabletformisnot absorbeduntilthetabletdisintegratesandthedrugparticlesare dissolved, itwouldbeunderstandableifonly theabsorptionof tabletswasinfluencedbyfoodcomparedwithenalaprilsolution, notviceversa.Butperhaps, whenusinganoralsolution,more enalaprilcanbindtofoodparticles,leadingtoalowerpercentage availableforabsorption.

Hepaticimpairmentcouldtheoreticallyalterthemetabolismof enalapriltoenalaprilatandthetransportofenalaprilatoutofthe hepatocyte.TheabundanceofCES1incirrhoticliversisreducedto 25%incontrollivers[36].Achangeinhepaticmetabolismmight alsooccurinCKDduetotheinterferenceofuremictoxinswith transcriptionalactivation,causinginhibitionofdrugtransporters and drug-metabolizing enzymes [37].in vitrodata suggest that diseasestatuscanalsoinfluenceCES1hydrolyticactivity,because interleukin-6(IL-6)decreasedtheexpressionofCES1andCES2by upto60%[38].Despitesuchareduction,invivostudies confirm-ingthehypotheticallylowerenalaprilatlevelsarenotavailable.

Becauseenalaprilat isrenallyexcreted,renalimpairment, de-fined as a GFR below 30ml/min/1.73m2, willresult in higher enalaprilatserumconcentrations.Indeed,thiswasshownbyKelly

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etal.in24patientswithdifferentdegreesofrenalfailure(GFR5– 88ml/min/1.73 m2₎ _[39]_. _Furthermore, _in _addition _to _higher

serumconcentrations,reducedrenalfunctionledtolongertimes to reach Cmax,because serum enalaprilat concentrations could

furtherincreasewhenexcretionwasdelayed.Tmaxincreasedbyup

to24h,andthehighestCmaxobservedwas214ng/mLatadoseof

10mg. This is four times higher than values observed in the absenceofrenalfailure[14].Becausethereisnoreasontoassume thiswillnotbeapplicabletochildren,dosereductionofenalapril inpaediatricpatientsmightbenecessarytopreventthe accumu-lationofenalaprilatandfurtherrenalinsufficiency.Whentaking theabove-mentioneddiseasefactorsinfluencingPKintoaccount, theeffectofACEinhibitortherapystillshowssignificant interin-dividual variability. We now focus on the impact of age on enalaprilPKandPDvariability.

Paediatric

PK

studies

WeidentifiedonlythreepaediatricPKstudies,includingatotalof 62childrenwitheitherhypertension[40]orHF[41,42].Thissmall numberofpatients,andinterstudyvariabilitylimitsconclusions onthePKofenalaprilandenalaprilatinchildrenandthepotential impactofageandotherco-variates.

All enalapril and enalaprilat levels were measured using a radioimmunoassay.Enalaprilatwasdirectlymeasured,and enala-prillevelswerededucedonthebasisofvaluesobtainedbeforeand after hydrolysis [27]. This radioimmunoassay method was the same as in the referenced adult PK studies [12,13,27,28] and wasatthetimedeemedtobeaccurateforenalaprilat concentra-tionsover2ng/mL[43].

Enalapril

PK

Two of the threestudies describedenalapril PK, in addition to enalaprilat(Table1).Inthe2001studybyWellsetal.,40 hyper-tensive children (aged 2 months to 15 years) received 0.07– 0.14mg/kgenalapriloncedaily,administeredasadispersed sus-pension[40].TheenalaprilTmaxoccurredapproximately1hafter

administration, compared with 0.5–1.5h as reported foradults [12,13].MeanCmaxvaluesrangedbetween24.6and45.4ng/mL

across the different agegroups.Cmax valuesin adultsreceiving

averagedosesof0.14mg/kgwere45–49ng/ml[12,13].

Nakamuraetal.describedthePKofenalaprilafterdosesof0.05 to0.3mg/kginchildrenwithCHF(n=12,age10daysto6.5years) [41].Asdescribedaboveforadults,oneneedstotakeintoaccount possible differences in PK in children with CHF versus other children.Theresultsarepresentednormalisedtoanenalaprildose of0.1mg/kg. EnalaprilT1/2was2.7 (SD1.4)hinchildrenolder

than20days(n=10,11observations),comparedwith1.6(SD1.5) hasreportedforadults[14,27].Furthermore,theAUC0–infinityin

children>20 dayswas82.7 (SD44.3)ng.h/mL, comparedwith 55.6 (SD5.7)ng.h/mLin adults[27].The T1/2andAUCin two

neonates<20daysofagewere10.3(SD5.2)hand268.7(SD138.9) ng.h/mL,respectively,basedonthreeobservations.

Enalaprilat

PK

IntheWellsstudy,enalaprilatAUC0–24handCmax,normalisedper

kgbodyweight,weresignificantlylowerinninechildrenwhowere between2and24monthsofagecomparedwith12childrenaged 12–16years[AUC0–24h131.4(95%CI91.9–187.9)ng.h/mLversus

272.7(95%CI197.3–377.0)ng.h/mLper0.1mg/kg,Cmax13(95%

CI9.2–18.4)ng/mLversus31.8(95%CI23.5–43.0ng/ml][40].No significantdifferencebetweentheotheragegroupswasobserved. Whencorrectedforbodysurfacearea,theAUCandCmaxdidnot

differbetweenagegroups.

Thepercentageofenalaprildoseexcretedintheurinewas calcu-latedonthebasisofmeasuredurinaryrecoveryofenalaprilat.This percentagemightserveassurrogatemarker ofCES1andhepatic transporteractivitybecauseitlargelyreflectsconversionofenalapril toenalaprilat[40].Themeanpercentageconversionofenalaprilto enalaprilatshowedgreatvariability.Thiswaslargestwithintheage groupofchildrenfrom1to24monthsofage,withCIrangingfrom 42.6to89.1%.Acrossagegroups,enalapriltoenalaprilatconversion proportionswere 64.7 to74.6% and did not differ significantly betweenagegroups.TheobserveddifferenceinAUCbetweenthe youngestandoldestagegroupsmightsuggestincreasedCES1and hepatic transporter activityin the youngest age group, butthe conversiondatacannotconfirmthishypothesis.Becausethepatient numbersaresmall,anage-relatedchangeineitherCES1metabolism orhepatictransportcanthereforenotbeexcluded.

Nakamuraetal.observedanormalisedenalaprilatAUC0–infinity

forchildren>20daysof138.4(SD69.2)ng.h/mLper0.1mg/kg enalapril[41].Becauseall buttwo ofNakamura etal.’ssubjects werebelowtheageof24months,thiscohortmightbecomparable inagetotheyoungestagegroupofWellsetal.[40].

InchildrenwithCHFaged>20daysto24months,theaverage T1/2ofenalaprilatwas11.1(SD4.3)h,whereasWellsreported,in

the whole cohort, T1/2 of enalaprilat up to 16.3h, with large

interindividualvariability,asshownin Table1[40].Inhealthy adults,T1/2rangesfrom3.8to11h,whereasinadultswithCHF,a

mean(SD)T1/2of6.8(SD2.5)hwasfound[32].

ThethirdPKarticlefrom1989describesadose-findingstudyin tenpaediatricpatients(aged6weeksto8months)withCHF[42].A doseescalationprotocolwasused,withdosagesaslowas0.02mg/ kginsomechildren.Theselowdosesresultedinahighproportion ofthe24henalaprilatserumsamples(fouroutofthetenchildren) beingbelowthelowerlimitofquantification.Consequently,no usefulPKparameterscouldbeobtainedfromthosechildren.Insix childrenreceivingthehighestdoseof0.08mg/kg,theserumT1/2

ofenalaprilatwas7.55(SD0.66)handtheCmaxwas12.7(SD2.9)

ng/mLper0.1mg/kgdoseofenalapril.

Overall,theavailablePKdataaretoolimitedtosupport with certainty an age-related effect on enalapril and enalaprilat PK. Lowerenalaprilatexposureafterbodyweight-normaliseddosingin younginfants,assuggestedbytheWellsstudy,couldbesupported bythedatafromthetwootherPKstudies,butalltogether,the smallpatientnumbersacrossawideagerangeandthedifference intheunderlyingdiseaseprecludedefinitiveconclusions.

TheunknowninterplayofthedifferentPKprocessesinvolvedin thedispositionofbothenalaprilanditsactivemetabolitefurther hamperssimpleextrapolationofknowledgeonthematurationof these processes to support the suggested age-related variation. CES1proteinabundanceincreasesfivefoldfromneonatestoadults [44].Atbirth,theGFRislow,andataroundtwoyearsofage,the GFRreachesitsmaximumvalueofaround3.2ml/min/kg; hereaf-ter,itdecreasestoreachadultvaluesfromtheageoffiveonwards [45].AlthoughdataontheontogenyofhepaticMRP4inhumans arelacking,ajuvenileratstudyshowedlowexpressionatbirthand

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an increase until day 60 of life [46]. Furthermore, the renal transportersinvolved in enalaprilat excretion arecurrently un-known.

Pharmacodynamics

Adults

Enalaprilat inhibits ACE, which leads to reduced formation of angiotensinII.Followinganenalaprildoseof10mginhealthy individuals,ACEinhibition(reflectedbythereducedgenerationof angiotensin II) was almost complete between 4 and 10h after administration.Accordingly,plasmareninlevelsincreased with maximumlevelsafter4h,andbothangiotensinIIandaldosterone levelsdecreasedandremainedlowupto10hafteradministration [1].TherelationshipbetweenACEactivityandplasmaenalaprilat levels,aswellasBPand plasmaenalaprilat levels,wasinversely proportional,as wasshown by de Leeuwet al. in hypertensive patients[47].

Duringdecompensatedcardiac failure,theRAASisactivated owingtoalowercardiacoutput,leadingtoadecreasein periph-eralvascularresistanceandadiminishedvolumeofthe extracel-lularfluid,but returns to normal when heart failure stabilises

[48].Aswould be expected, theformationof angiotensinII is decreasedinpatientsusingenalapril,leading tolowerlevelsof angiotensinII,lessactivationofACEandloweraldosteronelevels [49].

Children

DatasupportingtheincreasedactivityoftheRAASduringinfancy andchildhoodinhealthychildren(upto4yearsofage)havebeen previouslypublishedandarewidelyaccepted[50].Interestingly, andinasimilarpatterntoadults,afteronce-dailyadministration of0.25mg/kgenalapril,inhibitionofACEactivityineightinfants withCHF(aged3weeksto6months)was75.5%(SD12.2%)at4h after intake compared with ten healthy children without ACE inhibitortreatment[51].

AngiotensinIIconcentrationsdecreasedfrom115(SD67)pg/mL to60(SD30)pg/mLandplasmareninactivityincreasedfrom25(SD 24)ng/mL/hto45(SD37)ng/mL/hin35childrenwithCHF(aged1 monthto17years)afteranaverageof17daysoftreatmentwith enalaprilatanaveragedailydoseof0.24mg/kgtwicedaily[52].To thebestofourknowledge,noPDparametershavebeenmeasured duringenalapriltreatmentinchildrenwithhypertension.

TABLE1

PKofenalaprilandenalaprilatinchildrencomparedwithadults

Wellsetal.2001[40] Nakamuraetal.1994[41] Lloydetal.1989[42]

Agerangeandnumberofpatients 2months–15years:40 <20days:2

20daysto6.5years:10 21–39years:7 6weeks–8months:10 Diagnosis Hypertension CHFa CHF Dose 0.07–0.14mg/kg Children:0.05–0.3mg/kg Adults:10mg 0.02–0.08mg/kg Pharmacokineticparametersofenalapril

Cmax,mean 24.6_–45.4ng/ml _– _–

Tmax,mean 1h – –

AUC0–infinityinng.h/mL,mean(SD) – <20days:268.7(139.9) –

>20days:82.7(44.3)

T1/2inh,mean(SD) – <20days:10.3(5.2) –

>20days:2.7(1.4) Pharmacokineticparametersofenalaprilatb

AUCper0.1mg/kg(ng.h/mL)

Wells:AUC0–24h,geometricmean(95%CI) Nakamura:AUC0-1,mean(SD)

2–24months 131.4(91.9–187.9) <20days:691.5(225.6) >20days:138.4(69.2) – 2–6years 140.7(98.4–201.3) – 6–12years 176.3(125.6-247.5) – – 12–16years 272.7(197.3–377.0) – – Adults – 245.7(61.8) – Cmaxper0.1mg/kg(ng/mL) Wells:geometricmean(95%CI) Nakamura:mean(SD) Lloyd:mean(SD) 2–24months 13(9.2–18.4) <20days:5.3(3.0) >20days:9.0(4.7) 12.7(2.9) 2–6years 18.4(13–26.1) – 6_–12years 22.7(16.3_–31.7) _– _– 12_–16years 31.8(23.5_–43) Adults _– 30.3(14.0) _– Tmax(h)

Wells:median(95%CI) Nakamura:mean(SD) 2_–24months 6.0(4.0_–8.0) _<20days:? >20days:7.3(2.4) 4 2–6years 5.0(3.1–6.9) – 6–12years 5.0(4.0–6.0) – – 12–16years 4.0(3.0–5.0) – – Adults – 3.7(1.4) – T1/2(h)

Wells:mean(95%CI) Nakamura:mean(SD) Lloyd:mean(SD) 2–24months – <20days:? >20days:11.1(4.3) 7.55(0.66) 2–6years 15.37(9.45–28.07) – 6–12years 16.31(10.98–20.44) – 12–16years 14.61(10.22–23.00) – Adults – 5.3(1.6) – a

Abbreviations:AUCinfinity,areaunderthecurve;CHF,congestiveheartfailure;Cmax,maximumserumconcentration;T1/2,eliminationhalf-life;Tmax:,timetomaximumconcentration. b

AggregatedAUCandCmaxvaluesofenalaprilatreportedbyWellsandLloydetal.werenormalisedtoadoseof0.1mg/kgperagegroupinordertofacilitatecomparisonbetween

studies.Usedformulas:AUC,dose/CL;concentration,dose/CLandassuminglinearkineticsforTmaxaswellasT1/2.

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T ABLE 2 Pa ediatric enalapril trials Indication (number of trials) Referenc e Number of patients Ag e o f population Exact indication Dosage and type of formulation (dura tion) T ype of trial Le vel of e vidence a [142] Effect Hyper tension (9) Burrello et al. 2018 [53] 2378 Median of 12 years Hyper tension Mean 0.08 mg/kg/day of oral suspension once daily (2 weeks) Meta-analysis 1a Together with lisinopril, enalapril was superior to placebo in reducing SBP b and DBP compared to other antih yperte nsiv e agents W ells et al. 2002 [54] 110 6– 16 years Hyper tension Mean 0.08 mg/kg/day of oral suspension once daily (2 weeks) RCT (double blind) 1b Adm inistration of enalapril led to an effective lowering o f B P ; the dose – response relationship fo r enalapril had a negative slope and w as linear ove r the chosen dosing range Di Salvo et al. 2016 [56] 51 (25 enalapril) 6– 20 years Aortic coarctation repair with h yper tension 0.08 –0.6 mg/kg/da y, tablet, once daily (12 months) RCT comparing enalapril with atenolol (open label) 1b Reduction in 24 h SBP (135 (SD 6) mm Hg v ersus 127 (SD 7) mm Hg , p = 0.001) + significant reduction in left v entricular mass index Schaef er et al. 2011 [55] 300 6– 17 years Hyper tension Dependent on weight; tablet of 10, 20 or 40 mg/day , once daily (12 weeks) Randomised, double-blind , parallel-group , active-controlled study with V alsart an 1b Significant reduction in m ean sitting SBP ( 11.8 mm Hg) and DBP ( 7.9 mm Hg) compared with baseline (p < 0.0001) Schilder et al. 1995 [57] 1 P reterm infant Neonatal hypertension 0.1 mg/kg orally Case study 4 Sev ere hypotension and renal failure Mason et al. 1992 [58] 2 Neonates Neonatal hypertension IV enalapril, 0.1 mg/kg/da y divided ev ery 6 h Case study 4 Case 1: v entricular shortening fraction improv ed from 8% to 20%. Case 2: MAP decreased from 67 mm Hg to 40 mm Hg. Marcadis et al. 1991 [59] 1 3 da ys Neonatal hypertension IV enalaprilat, 0.01 mg/kg single dose Case report 4 Mean BP decreased from 91 to 51 mm Hg W ells et al. 1990 [60] 10 26 –36 weeks gestational age (post-conception age 29 –44 weeks) Neonatal hypertension Enalaprilat IV , 5.2 –28.8 m g/kg/24 h, median dosing inter v a l 1 2 h (2 –17days) Case study 4 Significant reduction in m ean arterial pressure (MAP) (p < 0.05) Miller et al. 1986 [61] 14 6 weeks –18.5 years V arious renal diseases and hypertension 2.5 –30 mg/day orally (5 –12 months) Case study 4 Normal BP for age was achiev ed in all 14 children; however ,eight children required the addition of a diuretic Hear t failure (14) Hsu et al. 2010 [71] 230 20.1 (SD 8.9) days Single v entricle phys iology 0.1 –0.4 mg/kg/da y; exact formulation not described (14 months) Double blind RCT with placebo 1b No improv ement in somatic growth, v entricular function or heart failure severity Kouatli et al. 1997 [81] 18 14.5 (SD 6.2) years After F ontan procedure 0.2 –0.3 mg/kg/da y once daily (10 weeks) Double blind placebo-controlled crossover trial 1b Enalapril administration fo r 1 0 w eeks did not alter abnormal systemic v ascular resistance, resting cardiac index, diastolic function or ex ercise capacity Mori et al. 2000 [67] 24 (3 enalapril) 0.3 –16 years Aortic or mitral regurgitation 0.15 –0.4 mg/kg/da y [mean 3.4 (SD 2.0) years] Prospective cohort (randomised) 2b Mean change in Z-value fo r LV end diastolic dimensions 0.25 (SD 0.33) fo r ACEi group versus 0.42 (SD 0.48) fo r control group (p = 0.0007) Mean change in mass normalised to growth: 72 (SD 89)% of normal fo r the ACEi group vs. 37 (SD 35)% of normal fo r control group (p = 0.0007) Le v ersha et al. 1994 [72] 63 4 years (SD 5.4 months) Congenital and acquired heart disease 0.04 –0.94 mg/kg/da y, once , twice or three times daily (1 day –3 years) Prospective cohort 2b 58% of all patients had improv ed signs of CHF .T he dose receive d b y those who improv ed was significantly greater (p = 0.04) than that receiv ed by those who showed no change. W ebster et al. 1992 [73] 26 6 m onths –15 years Intracardiac shunts Enalaprilat IV 0.06 mg/kg (30 min) Prospective cohort 2b Mean pulmonary –systemic flow ratio decreased from 2.9 (SD 0.3) to 2.4 (SD 0.3) (p < 0.05) and the mean left-to-right shunt from 7.4 (SD 0.8) to 5.9 (SD 0.7) l/min/m 2(p < 0.02) after enalapril treatment Sluysmans et al. 1992 [74] 8 < 10 months Isolated large v entricular septal defect Enalaprilat IV 0.02 mg/kg (15 min) and enalapril 0.16 mg/kg orally once daily (7 days) Prospective cohort 2b IV administration: absolute left-to-right shunt decreased 27% [7.5 (SD 6.3) to 5 (SD 3.7) l/min/m 2, p < 0.05]. Systemic blood flow did not change. Pu lmonary blood flow decreased 15.5% (p < 0.1). Mean decrease of aor tic mean pressure was 9 % (66 (SD 9) to 61 (SD 9) mm Hg , p < 0.0001). Oral administration :six patients had increased weight gain [82 (SD 59) to 166 (SD 94) g/week] and bottle fe eding [milk, 139 (SD 16) to 158 (SD 13) ml/kg/da y; p < 0.05] Seguchi et al. 1990 [52] 35 1 m onth –17 years CHF 0.11 –0.8 mg/kg/da y orally , twice a day (7 –44 days) Prospective cohort 2b Significant decrease in left v entricular end-diastolic dimension, hepatomegaly and cardiothoracic ratio (p < 0.05) Rheuban et al. 1990 [75] 11 1– 13 months CHF secondar y to left-to-right shunt lesions IV enalaprilat 0.01 mg/kg , single dose (20 min) Prospective cohort 2b Significant reduction in systemic v ascular resistance [18.1 (SD 4.7) to 14.2 (SD 3.5) W ood units *m 2; p < 0.001]. Reduction in pulmonary/s ystemic blood flow ratio (p = non-significant). Lewis et al. 1993 [76] 81 (of which 27 A C E inhibitor and two enalapril) 3.6 (SD 0.6) years Dilated cardiom yopath y Dose not mentioned . (2 years) Retrospective cohort 2b Signi ficantly better surv iv al during the first year (p < 0.05) with continuation of this trend throughout the second year (p = 0.06). Beyond 2 years , this diff erence was no longer significant. Robinson et al. 2002 [77] 9 13.8 (SD 3) years Transposition of the great ar teries s/p intra-ar terial switch after intra-ar terial baffle 0.1 –0.5 mg/kg/da y, rounded to the nearest 2.5 mg (12 months) Case study (prospective) 4 N o improv ement in exercise performance in patients with transposition of the great ar teries in whom the intra-atrial baffle procedure had been performed Eronen et al. 1991 [78] 8 1.5 –11.2 years CHF and dilated cardiomyopathy 0.5 mg/kg/da y, orally once daily (5 days) Case study (prospective) 4 Diminished afterload , reflected by a decrease in mean SBP from 104 to 96 mm Hg (p = 0.054), and a decrease in heart size from 582 to 523 ml/m 2 (p = 0.09) Lipschultz et al. 2002 [79] 18 1– 18.1 years V entricular dysfunction due to dox orubicin treatment 5– 40 mg/da y; exact formulation not described (10 years) Case study (retrospective) 4 P ro gressive improv ement towards normal v alues of LV dimension, afterload , fractional shor tening and mass in the first 6 y ears of enalapril treatment F renneaux et al. 1989 [80] 8 4 da ys –12 weeks Severe heart failure Suspension of crushed tablet, 0.12 – 0.43 mg/kg/da y once daily (2 weeks) Case study 4 Mean (SEM) liver size had decreased from 2.3 (0.36) cm to 1.2 (0.24) cm below the costal margin, mean respiratory rate had fallen from 63 (3.2) to 53 (2.8) breaths per minute .The mean heart rate increased from 136 (6.4) to 143 (4.2) beats per minute and the mean SBP fell from 88 (4.0) mm Hg to 82 (6.5) mm. No p -valu es were reported. Li et al. 2011 [143] 5 Mitral regurgitation after atrioventricular septal defect repair Double-blind RCT Sev enteen months after the start, the study was terminated because of low patient accrual 6 www.drugdiscoverytoday.com Reviews KEYNO TE REVIEW

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Drug Discove ry Toda y V olume 00, Number 00 A ugust 2020 REVIEWS DR UDIS-27 62; No of Pages 14 Please cite this article in press as: Smeets, N.J.L . et al. Pharmac ology of enalap ril in children : a re vie w , Drug Discov T oday (2020), https:/ /doi.org/10.1016/j.drudis.2020.0 8.005 TABLE 2 (Continued ) Indication (number of trials) Reference Number of patients

Age of population Exact indication Dosage and type of formulation

(duration)

Type of trial Level of

evidencea

[142] Effect

Kidney disease (13) Webb et al. 2012 [88]

268 (134 enalapril) 10.4 (SD 4.7) years Children with proteinuria Suspension or tablet, mean dose

0.26 mg/kg (12 weeks)

Double-blind RCT 1b The LS percent mean reduction from baseline in the urinary protein–

creatinine ratio was 40.45%. The LS mean change from baseline in eGFR

was 7.0 ml/min per 1.73 m2_{(both after 3 years).}

Webb et al. 2013 [87]

27 (12 enalapril) 1–17 years Alport disease Suspension or tablet, 0.07–0.72 mg/kg/

day (12 weeks)

Double-blind RCT 1b The LS mean percent change from week 12 in urinary protein LS mean

change from week 12 in eGFR was9.1 ml/min/1.73 m2_{in the enalapril}

group Caletti et al. 2011

[89]

46 (14 enalapril) 2.08–13.89 years Post-diarrhoea HUS 0.18–0.27 mg/kg/day single oral dose (7

months)

Double-blind RCT 1b Decrease in proteinuria with enalapril was 66.3%. Significant decrease SBP

of 12% (p< 0.023) after treatment with enalapril (no change after placebo

or losartan). Bagga et al. 2004

[90]

25 1–16 years Steroid-resistant nephrotic

syndrome

0.2–0.6 mg/kg/day (2 8 weeks) Randomised crossover trial (open label) 1b High-dose enalapril (0.6 mg/kg/day) was associated with a significant

reduction in urine albumin-to-creatinine ratio (p< 0.01)

Hari et al. 2013 [91]

41 (20 enalapril) 2–18 years CKD 0.4 mg/kg/day tablet once daily (1 year) Open-label RCT 1b The rate of decline in GFR was 3.0 (SD 4.2) in the enalapril and 4.2 (SD 5.1)

ml/min/1.73 m2_{in the non-enalapril group (p = 0.51)}

Sasinka et al.

1999[92]

48 (17 enalapril) Unknown Proteinuric children Unknown (8 weeks) Retrospective study 2b Proteinuria decreased from 1.32 (SD 0.23) to 0.53 (SD 0.11) and 0.44 (SD

0.07) g/day on the 4th and 8th week of treatment Proesmans et al.

2000[93]

7 5.15–13.75 years Alport syndrome Tablet, 0.13–0.29 mg/kg/day (24

months)

Case study (prospective) 4 Marked reduction in urinary protein excretion with a nadir of 23% (52 mg/

kg to 12 mg/kg per 24 h) of the baseline at 18 months; no p-value reported Guez et al. 1998 [95] 1 22 months (born at 35 weeks gestation) Finnish-type congenital nephrotic syndrome

0.8 mg/kg/day (1 month) Case study (prospective) 4 Serum protein concentration was maintained without the need for

albumin infusions (no p-value reported) Proesmans et al.

1996[94]

5 7–17 years Various renal diseases 0.5 mg/kg per day (24 months) Case study (prospective) 4 Median decrease in proteinuria of 52% (no p-value reported)

Trachtman et al.

1988[96]

8 (1 enalapril) 5–22 years Proteinuria unresponsive for

standard therapy

2.5 mg/day (undefined) Case study (prospective) 4 BP declined to the normal range in all cases and achieved a mean value of

112/73 mm Hg (p< 0.005)

Caletti et al. 2013 [97]

17 0.25–5.33 years Diarrheal HUS 0.20–0.56 mg/kg/day (5.92 years) Case study (retrospective cohort) 4 Decrease in proteinuria with enalapril was 58% (p = 0.023)

Fitzhugh et al.

2005[98]

3 14–17 years Sickle cell nephropathy 5–7.5 mg/day (3.0 1.3 years) Case study 4 Increase in serum albumin levels from 2.8 (SD 0.8) g/dl to 3.9 (SD 0.3) g/dl

(no p-value reported) Lama et al. 2000

[99]

6 ? Steroid-resistant nephrotic

syndrome

0.3 mg/kg/day (2 years) Case study 4 In 71.4% enalapril therapy resulted in an important reduction of

proteinuria a

Level of evidence according to Johansen et al.: systematic reviews and meta-analyses of RCTs (1a), RCT (1b), non-randomised controlled trials (2a), cohort studies (2b), case-control studies (3), case studies, expert opinion. b

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; BP, blood pressure; CHF, congestive heart failure; CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HUS, haemolytic uraemic syndrome; IV, intravenous; LS, least squares; LV, left ventricle; MAP, mean arterial pressure; RCT, randomised controlled trial; SBP, systolic blood pressure; SEM, standard error of the mean.

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Indications

Inthe paediatricpopulation, enalaprilisprescribedforpatients with hypertension, CHF and CKD (Table 2). We identified 36 articlesreportingtheclinicaleffect ofenalaprilinchildrenwith (oneof)thesethreedifferentdiagnoses.Therewaslarge heteroge-neity both in the study methods and the outcome measures; therefore,the resultsaredescribedbelow by underlyingdisease aswellaslevelofevidence.

Hypertension

Children

Nine articles described the effect of enalapril in hypertensive patients,andonemeta-analysisstudiedthepharmacological treat-ment of arterialhypertensionin childrenand adolescents [53]. Togetherwithlisinopril,enalaprilseemstobesuperiorinreducing systolicBP(SBP)anddiastolicBP(DBP)comparedwithother anti-hypertensiveagents.However,itisimportanttomentionthatthe conclusion of this meta-analysis is solely based on one dose– response study investigatingenalaprilin 110hypertensive chil-drenaged6–16years[54].Enalaprilwasadministeredasa suspen-sion,and patientswererandomisedto receivea low,middleor highdose.Forchildrenbelow50kg,thiswas0.625,2.5or10mgof enalapriloncedaily,respectively.Above50kg,1.25,5or20mgof enalaprilwasadministered.Ameandoseof0.08mg/kgseemedto beeffectiveatloweringBPwithin2weeksinmostpatients.Higher doseswereassociatedwithagreaterreductioninBP.

Theothersevenpaediatricenalaprilstudieswereexcludedinthis meta-analysisbecausetheydidnotcompareenalapriltoplacebo. Onerandomisedcontrolledtrial(RCT)comparedtheeffectiveness ofvalsartan,anangiotensinIIreceptorblockingagent,toenalapril in300hypertensivechildrenaged6–17yearsafteraplaceborun-in period[55]. Dosing was basedon bodyweight, with doses up to 40mg ofenalapriland320mgofvalsartan.Thestudyfoundareductionof 14.1 (SD 8.5) mm Hg in mean BP from baseline in the enalapril group. Asimilarreductionfrombaselinewasseeninthevalsartangroup (p< 0.0001).In51childrenaged6to20yearsofageafteraortic coarctationrepairandhypertension,thesuperiorityofenalaprilto atenolol,abetablocker,wasshown.Thiswasbasedonthereduction of theleft ventricularmassindex aswell as24hSBP [56].The remainingfivestudieswereallcasestudies orserieswithoneto 15patients,andsuggestedasimilartrendwithareported (statisti-cally)significantdecreaseinBPaftervariouslengthsoftreatment [57–61].

Tofurtherexplorethedose–responserelationshipofenalapril,a PK/PDmodelwasdevelopedtopredictitsefficacyinchildrenaged 0–6yearsusingBPasthePDendpoint[62].Atwo-compartment modelincorporatingweightwasbuilttopredictadecreaseinDBP usingthreedatasets,twoofwhichwerefromchildren[40,54].On thebasisofmodelpredictions,researcherssuggestthatthedose– responseofenalaprilissimilarinchildrenbetween1monthand6 yearsofagecomparedwiththoseolderthan6yearsofagewhen looking at the reduction of DBP after 2 weeks of treatment. However,thesedataneedfurthervalidationbecausenoPDdata ofchildrenbelowtheageof6yearswereused.

Nexttoage-relatedchangesinPD,theeffectofgenderorsexual maturity(Tannerstage)wasalsoinvestigatedanddidnotexplain variabilityintheantihypertensiveeffectofenalaprilin110 paedi-atrichypertensivepatients,aged6–16years[54].

In African American adults, it is well established that ACE inhibitors are less effective in lowering BP, which is probably explained by lower renin levels in this population [63]. In a meta-analysis of six paediatric antihypertensive trials, BP de-creasedsignificantlyfrombaselinein Caucasian(SBPp= 0.003, DBPp< 0.0010),butnotinAfricanAmericanchildren(SBPp= 0.139,DBPp=0.397)[64].However,althoughitisnotmentioned specifically for the paediatric population, the efficacy of ACE inhibitorsispromisingevenincasesofenhancedreninsecretion (hyper-reninaemichypertension)[65,66].

Inconclusion,moderatestrongevidencesupportstheefficacy ofenalaprilintreatinghypertensioninCaucasianchildrenolder than6yearsofage.Foryoungerchildren,dataarescarce;for non-Caucasianchildren,theefficacymaybelower.

Heart

failure

Adults

Enalaprilhasapositiveeffectonheart-failureparametersbeyond itsBP-loweringeffect[67].Becausechronicvolumeoverloadwill lead to ventricular dilatation and myocardial hypertrophy in certainformsofheartfailure,irreversiblestructuralandfunctional damagewilloccur.Byreducingcardiacafterload,ACEinhibitors havebeenshowntoreducetheextentofdilatationand develop-ment of redundant cardiac musclemass, thereby reducing left ventricle(LV)volumeoverloadandimprovingLVfunction[3].As wellasareductioninafterload,thiseffectcanbeexplainedbythe inhibition of hydrolysis of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP),whichisanimportantinhibitorofstemcell prolifera-tion.ByraisingAc-SDKPconcentrations,ACEinhibitionleadsto reducedcardiaccell proliferation, inflammatory cell infiltration andcollagendeposition[68].Thisalsoexplainswhyenalaprilis beneficialinseveraltypesofheartfailure.

AlthoughthepositiveeffectofACEinhibitortherapyinadults withheartfailureiswellestablishedandACEinhibitortherapyhas amajorplaceinthetherapyofadultheartfailureinbothEurope andthe UnitedStates[69,70],thiseffect islessapparentinthe paediatricpopulation,inwhichstudiesshowconflictingresults.

Children

Fourteenstudies addressed the efficacyof enalapril in children withheartfailure;twoofthesestudiesweredouble-blind placebo-controlledrandomisedtrials.ThesetwoRCTscomparingenalapril toplacebowereconductedinpaediatricheartfailurepatientswith single ventricle physiology [71]. These children have a special haemodynamic situation, and the clinical effects of enalapril mightnotbecomparable tootherformsofheartfailure. These studiesarethereforediscussedattheendofthissection.

Sixprospectivecohortstudiesinvestigatedtheeffectof enala-pril,andtheyallshowedasignificanteffectonseveralheartfailure parameters(Table2).In24patientsaged0.3–16yearswithaortic ormitralregurgitation,treatmentwithenalapril(oranotherACE inhibitor)ledtoadecreaseinbothposteriorwallthicknessandLV mass[67].Similarly, amongchildren[meanage4 years(SD5.4 months)]withCHF,39outof67treatmentperiodsin63patients showed animprovement in clinical parametersafter treatment withenalapril[72].Althoughnoclinicalendpointswereassessed in26childrenaged6monthsto15yearswithalargeventricular septaldefectinthestudyofWebsteretal.,theyfoundthatafter

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startofenalapril,aorticandpulmonaryarterypressuredecreased by20%[73].

Ineightchildrenwithanisolatedlargeventricularseptaldefect (aged<10months),treatmentwithenalaprilresultedinimproved bottlefeedingandincreasedbodyweight[74].In35children(aged 1monthto17years)withmitraloraorticregurgitationfollowing intracardiacrepairorwithdilatedcardiomyopathywhoreceived enalapril,hepatomegalysignificantlydecreasedaswellas cardio-thoracicratio,heartrateandBP.LVend-diastolicdimensionalso decreased[52].Furthermore,in11children(aged1–13months) with CHF secondary to a left-to-right shunt, systemic vascular resistance was significantly decreased (18.1 (SD 4.7) to 14.2 (SD3.5)Woodunits*m2_,_p_<_0.001)_after_treatment_with_enalapril.

However,thereductioninpulmonary/systemicbloodflowratio wasnotsignificant[75].

In aretrospectivestudyin 81children(meanage3.6(SD0.6)years) withadilatedcardiomyopathy,27childrenweretreatedwithACE inhibitoralone(enalapriln=2,orcaptopriln=25)versus conven-tionally with digoxin and diuretics (n=54). Both captopril and enalapriltreatmentshowedastatisticallysignificantbettersurvival rateduringthefirstyearcomparedtotheothergroup(p<0.05)[76]. Last,inthreeoutoffourreportedcaseseries,enalapriltherapy showed positive outcomes. The results of these studies can be foundinTable2[77–80].

Thelargest RCTonenalaprilwasperformedin childrenwith singleventriclephysiology[71].Enalaprilatanoraldoseof0.4mg/ kg/day given in two divided doses did not improve somatic growth,ventricularfunctionorheartfailureseverityin230infants (meanage20days)withasingleventriclethathadstablesystemic and pulmonary blood flow [71]. Based on the hypothesis that increasedsystemicvascularresistanceandimpaireddiastolic func-tionmightcontribute to decreased exercisecapacity, a double-blindcrossovertrialwasperformedin18post-Fontanprocedure patients(age14.5(SD6.2)years,doseof0.2–0.3mg/kg/dayfor10 weeks).Again, enalaprildid notimprove exercisecapacity, sys-temicvascularresistance,restingcardiacindexordiastolic func-tion[81].However,itisimportanttonotethatpatientswithCHF wereexcludedfromthisstudy.

Asdescribedabove,theonlytwoRCTsperformedinchildren withheartfailureinpost-Fontan procedurepatients orpatients withsingleventriclephysiologyfailedtoshowaneffectof enala-prilonechocardiographicindicesorclinicaloutcome.Yetthese findingsneedtobeinterpretedwithgreatcaution.Inpatientswith singleventriclephysiology,theindicationforACE-inhibitor ther-apy isnot clearbecause thisis a circulation with a potentially underloadedsystemicventricle,especiallyafterFontan comple-tion.Butdespitetheabsenceofevidence,ACEinhibitorsarestill usedinalargeproportionofthesepatients,partlyduetopotential limitations of these studies [82].In the Hsu et al. study, most patients(80%)hadpreservedventricularfunctionintheabsence ofneurohormonalactivationatbaseline,andsystolicheartfailure isonlyalatemanifestationandthusunusualinthispopulation [83,84].Inaddition,therewasahighrateofdrugdiscontinuation, andtargetdoseswerenotachievedinallpatients.Furthermore,as thepaediatricPKstudiessuggest,dosagesof0.07–0.3mg/kg/dayin childrenlessthan2yearsofagemightnotreachasimilarlevelof enalaprilatexposureasinadults[40–42].IntheHsuetal.study,the enalapriltargetdosewas0.4mg/kg/day.Also,intheKouatlietal.

study,enalaprilwasdosedat0.2–0.3mg/kg/dayinchildrenwitha singleventriclephysiology[81].

Studiesthatshowedatherapeuticeffectofenalapriloftenalso included patientsabove theageof 12years[52,56,67,73,77,78] and/ordirectlyadministeredenalaprilat[73–75].Hence,inorder toinvestigatetheeffectofenalaprilinchildrenwithheartfailure, newstudieswithhigherdosagesmaybeneeded.Untilthen,lowto moderatelevelofevidencesupportstheefficacyofenalaprilfor paediatricheartfailure.Forchildrenwithasingleventricle physi-ologyspecifically,thedataarelesssupportive.

Chronic

kidney

disease

Althoughitwasinitiallydevelopedasanantihypertensivedrug, enalapril is prescribed in patients with CKD with the aim of reducingproteinuriaand therebyimprovingrenalsurvival[85]. Its positive effect on kidney survival can be explained by two important factors [4]. ACE inhibitors in general decrease the pressurewithintheefferentarterioleandtherebythe intraglomer-ular pressure. Furthermore, inhibition of cytokine production resultsinlessglomerulosclerosisandlessfibrosis.However,itis important toconsiderthedifferencesinaetiologiesofCKD, be-causethecausesvarysignificantlybetweenadultsandchildren;in thelatter,anon-glomerularoriginofCKDismorecommon.

Children

ACEinhibitorsareusedin80%ofchildrenwithCKDofglomerular originandonlyin47%ofthosewithnon-glomerularCKD[86].In total, 13studiesdescribedtheuse ofenalaprilin childrenwith variouskidneydiseases.Threedouble-blindRCTswereperformed in341childrenintotal,aged1–17years,andtheyallreporteda significantdecreaseinproteinuria[87–89].Intwootheropen-label trialsin66childrenwithAlportdiseaseorpost-diarrhoea haemo-lyticuraemicsyndrome(HUS)aged1–18years,enalapril signifi-cantly decreased proteinuria [90,91]. Furthermore, one retrospectivecohort[92]aswellasfourprospectivecasestudies [93–96]inpatientsaged22monthsto22yearsshowedasimilar resultandsupportedtheuseofenalaprilinthispopulation.Last, three retrospective case studies also investigated the effect of enalapril, and all reported a positive effect on proteinuria in childrenaged0.25–17years[97–99].

Takentogether,thesestudiesprovideamoderatelevelevidence tosupporttheuseofenalapriltoreduceproteinuriainchildren with CKD. Whether enalapril is alsobeneficial for clinical end points such as dialysis-free survival or mortality remains un-known.

Adverse

events

Inadults,themostcommonadversereactionsseenwiththeuseof enalaprilarehypotension,renalfailure,hyperkalaemia,coughand angioedema[100].WhetherACEinhibitor-associatedkidney fail-ure is caused by direct nephrotoxicity, renal efferent arteriolar vasodilatation or hypotensionand lowrenalperfusion remains unclear[101].Coughisconsideredtobeafrequentsideeffectof ACEinhibitoruse,becauseitoccurredin13.5%ofallpatientson ACEinhibitortherapy,butonly37%ofthesecasescanbe attrib-uted solely to the use of ACE inhibitors [102]. Also, patients suffering from allergic reactions to one ACE inhibitor have a relativecontraindication toanotherACE inhibitoraswellasto

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angiotensinIIreceptorblockers.However,forangioedema,alow incidenceofcross-reactivityisreported(_<10%)[103].

Inchildren,hypotension,impairedrenalfunctionand hyper-kalaemia are the most commonly reported side effects of ACE inhibitors [104].Ina systematicreviewof11reports coveringa total of 1050 paediatric heart failure patients taking enalapril, hypotensionwasreportedin0–19%ofcases,renalfailurein 0– 29%andhyperkalaemiain0–13%[104].Articlesthatonly includ-edpatientstreatedwithcaptoprilwereexcluded.Reported differ-ences across studies can be(partly)explained by differences in adverse event definitions. There was no relation to dose, and neitherangioedemanorcoughwasreported.

Furthermore, the use ofACE inhibitors is notrecommended duringthesecondorthirdtrimesterofpregnancybecauseoftheir potentialfoetotoxicity[105].Thiscanbeexplainedbysuppression ofthefoetalRAAS,whichseemstodisruptfoetalvascular perfu-sionandGFR.LittledataareavailableregardingtheuseofACE inhibitorsduringthefirsttrimester.Animaldatadidnot demon-strateateratogeniceffect,andhumancasereports(n=9)didnot recordany embryo-foetal or postnataloutcome when enalapril exposurewaslimitedtothefirsttrimester[105,106].

We identified four morearticles describing adverse eventsin childrenusingenalapril.Onecasereportedangioedemaand hyper-tensionina14-year-oldpatientwithsystemiclupuserythematosus who receivedenalapril at an unknown dose for threeyears[107]. One paediatric cohort study of 42 patients (median age 7.6 years) reported persistent isolated cough in 17% of patients using an ACEinhibitor,ofwhichthemajorityusedenalapril[108].Cough resolvedwithindaysafterdiscontinuingtherapy.Furthermore,in thestudyof Seguchi et al. (n=35), acute renalfailuredevelopedin a 3-month-oldinfantoneday afteradministration ofenalapril,and hyperkalaemiaoccurredinfourchildren(12%ofthestudy popula-tion)[52].Allfiveadverseeventsresolvedafterdiscontinuationof enalapril.Althoughadverseeventswereprospectivelymonitoredin thestudy ofWebsteretal.[73],noadverse reactionoccurredin the26 childrentakingenalapril.Youngchildrenseemtobeatanincreased riskofadversereactionsrelatedtoacutekidneyinjury(AKI)induced by an ACE inhibitor because of their lower GFR and impaired autoregulationofrenalbloodflow[104].Morespecifically,children ofyoungagewhoarepronetodehydration,eitherowingtothe concomitant use ofdiureticsor gastro-enteritis,seemto beat a higherriskofdevelopingAKI-relatedadverseevents.

Inconclusion,enalaprilseemstohaveasimilarsafetyprofilein children compared to adults, but the incidence of cough and angioedema seemsto bemuchlower, althoughnotcompletely absent. To define the proportion of placebo-adjusted cases of coughinchildrenonACEinhibitors,furtherstudiesareneeded.

Drug

–drug

interactions

Adults

Thereareseveralcompoundsthatcanchangeefficacyandsafety whentakingenalapril,anddoseadjustmentsmightbenecessary whentakingenalapriltogetherwithotherdrugs.Thisincludesthe concomitantuseofenalaprilwithdiureticsorothermedications workingontheRAAS,suchasangiotensinIIreceptorblockersor renin inhibitors (aliskiren). One in three adult patients with chronic heartfailure developedAKIwhen ACE inhibitors were co-administered with diuretics, compared with only 2.4% of

patientswhowereonACEinhibitoralone[109].Duetoapossible decrease in GFR, caution is warranted when primarily renally cleared medication that has a narrow therapeutic index (i.e., digoxin) or that increases the risk of AKI (non-steroidal anti-inflammatory drugs)isco-administered. To decrease therisk of developinghyperkalaemia,nopotassiumsupplementsshouldbe administeredatthesametime.

Children

Scantdataareavailableaboutpotentialdruginteractionsandtheir severityinchildren.Aninteractiondescribedforadultsisusually alsorelevantforthepaediatricpopulation.However,the magni-tudeofthesedrug–druginteractionscandiffergreatlyinchildren whencomparedtoadultdata,becausetheextentofanydrug–drug interactioncanbealteredbyphysiologicaldifferences[110].

Only twoarticlesdescribedenalapril interactionsin children,albeit inaveryspecificpopulation.Thetherapeuticeffectofallopurinolas wellashydroxyureaincreasedwhenenalaprilwasco-administered [98,111].Emphasizingtheimportanceofthepossibledevelopmentof hyperkalaemiawhentakingenalaprilwithpotassiumsupplements, theinteractionofenalaprilwithpotassiumchlorideiswithinthetop fivedrug–druginteractionsthatweremostfrequentlyoverriddenina paediatrichospital[112].ForACEinhibitoruseinchildren,the co-administrationoffurosemideisanindependentriskfactorfor devel-oping AKI in patients[35,113]. This risk factor is also supported by data frompharmacovigilancedatabases[101].

Drug

formulation

Inthepublishedstudies,childrenreceivedextemporaneousliquid formulationspreparedfromcrushedtabletsintendedforadults. Several problems can arisewhen using suchextemporaneously mademedications.Forexample,inadequatemixingorsettlingofa suspensionincreasestheriskofmedicationerrors[114].Therefore, several newformulations have been developedto ensure more precisedosinginchildren.First,anenalapriloralsolutionhasbeen developed,therebydecreasingtheriskofinappropriate prepara-tion and reducing the risk of inadequate therapy in children becauseasolutionrequiresnopreparationbynursesorparents. Also, as an alternative, enalapril oral dispersible minitablets (ODMTs)havebeendevelopedinthecontextoftheEUFramework Programme7labelling ofenalaprilfromneonates upto adoles-cents(LENA)project.Comparedtoanoralliquid,suchsolidoral dosage forms have greater stability, easier transportation and storage,and allowaccuratedosingwithoutthe needfora volu-metricmeasuringdevice[115].

The solution is bioequivalentto original tablet formulations [35].EnalaprilODMTsdisperseinthemouthandhaveaslightly higher Cmax but similar bioavailability to tablets [116]. These

newer formulations thus offer practical possibilities for more accurate dosing in children [35,117]. In addition, ODMTs can besuccessfullyadministeredthroughpaediatricnasogastrictubes (Charrie`re5)whendispersedin1mltapwaterwithout causing obstruction[115].ThePKandsafetyoftheseenalaprilODMTsare currentlybeingstudiedinchildrenwithheartfailure[118].

Whenoralintakeisundesirable,enalaprilatcanbeadministered intravenously.ThismakesenalaprilattheonlyintravenousACE inhibitorcurrentlyavailable,butavailabilityofthisintravenous (IV) formulation is limited from the global perspective, only

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including the United States, Canada,Germany, Poland, Czech Republic, Hungary and Ukraine. Moreover, its use is restricted toacutesituations[119].

Discussion

InthisreviewwehavesummarisedtheavailablePKandPDpaediatric data.Althoughtheefficacyofenalaprilforthetreatmentof hyper-tensionandproteinuria inCKDseemstobesupportedbyseveral studies,thelackofaBP-loweringeffectinAfricanAmericanchildren raisesthelimitationoftheseefficacydataofacrossethnicities. More-over,theevidenceforitsuseinchildrenwithheartfailureremains limited.Itisimportanttorealisethatapositiveeffectofenalaprilon heartfailureparametersin children withdifferent kinds ofheart failuremightexist,butthestudydesignsusedandthesamplesizes ofstudypopulationswerenotsufficienttodemonstratethese ben-efits.ThisproblemwasalsoaddressedbyRossanoetal.,whodescribed differencesbetweenpaediatric andadultheartfailurepopulations [120].Moreover,thepotential impactofage-related variationon enalaprilPK,assuggestedbythelimitedPKdataavailable,might furthercontributetovariationinobservedefficacyofenalapril be-tweenyounginfantsandadults.OnlylimitedPKdataareavailable, from62childreninthreestudies,coveringthepaediatricagerange fromneonatetoadolescent.Thesestudiessuggestthatenalaprilat exposuremightbelowerininfantscomparedwitholderchildrenand adults,butthedataacrossthepaediatricagerange(n=60),including neonates(n=2),aretoolimitedtodrawanyconclusions.Ifindeed younginfantsneedhighermg/kgdosestoreachsimilarexposureto adults, this might indicate that the lack of efficacy of enalapril observedinsomestudies,includingtheseyoungerageranges,might havebeenduetounderdosingandnotinefficacyofthedrug.

ManyyearsafterapprovalofenalaprilbytheUSFoodandDrug Administration,largeunexplainedinter-andintraindividual var-iabilityinPKandPDexists,andthemostprominentdeterminants ofthisvariabilityremaintobeestablished.Additionally,although somedeterminantsofvariationsinenalaprilPKwereidentifiedin theadultpopulation, includingthe effectofhypertension[30], CHF[31,32],renalimpairment[39],food[35]andrace[63],these factorsdodefinitelynotaccountforallinterindividualvariability observed,letaloneinthepaediatricpopulation.

Pharmacogenomics

Metabolomic and pharmacogenetic studies inchildren onACE inhibitorsmightbepromisingforfurtherunderstandingthe ob-servedvariation.Pharmacogenomicanalysisofpatients onACE inhibitortherapyhasledtothediscoveryofnewleadsfor explain-ingtreatmentresponses.Thereareseveralgeneticvariants associ-ated with ACE inhibitor effectiveness and safety, including mutationsin ACE[121].Also, becauseCES1 enzymaticactivity hasakeyroleintheconversionofenalapriltotheactive enala-prilat,theroleofCES1genevariationswasinvestigated.However, in healthy adults, variationsof the CES1gene (the number of functionalgenecopies)didnothaveaclinicallyrelevantimpact onthemetabolismofenalaprilandcouldnotexplainthe variabil-ityineffect[122].Thisfindingisnotinaccordancewithprevious published data, in which the AUC of another CES1 substrate (methylphenidate) was markedly increased in individuals with fourcopiescomparedwithcarriersofonlytwocopiesofthegene, suggestingdecreasedmetabolism[123].Theauthorsconcludethat

observeddifferencesinthePKofenalaprilmustbeexplainedbyPK differencesotherthanCES1genotypealone.

If,andtowhatextent,thosegeneticdifferencesalsocontributeto thevariabilityinoutcomesobservedinchildrenneedsfurtherstudy. Pharmacogenomicsinclinicalpaediatricsfacesseveralchallenges.For example, expression patterns of genes evolve during development and willthereforebedifferentovertime,whichmakesextrapolatingadult datatopaediatricclinicalcarechallenging[124].Onestudydescribed theassociationofRAAS-upregulationgenotypeswithfailureofreverse remodellingaftersuperiorcavopulmonaryconnectionsurgery,less improvementinrenalfunctionandimpairedsomaticgrowth[125]. This offers the possibilityof defining a high-risk groupof single ventriclepatientswhoareatriskoftherapyfailure.

Metabolomics

Similartopharmacogeneticprofiling,metabolomics,thestudyof smallorganicmoleculeswithinbiochemicalpathways,hasproven tobehelpfultounravelpartofthevariabilityinobserveddiseaseand responsetotherapyinadultpatients.Forexample,inadultswith heartfailure withpreservedejectionfraction,a metabolomic ap-proach has helped to reveal why the use of sildenafil was not beneficial in thisgroupof patients[126].Also,in patientswith therapy-resistanthypertension,specificmetabolitelevelshavebeen showntopredictfutureresponsetospironolactone[127].Numerous metabolicalterationsoccurintheheartduringadultheartfailure, involvingseveralmetabolicpathways[128].Someofthese metab-olitesshowedsignificantassociationswithBPinpatientsusingACE inhibitorsandcouldthereforebeofhelpindisentanglingpathways thataffecttheresponsetoACEinhibitors[129].

Thetherapyof(paediatric)heartfailureisstillmostlybasedon targeting the downstreameffects ofheartfailureinsteadof the underlyingcause.Heartfailureinchildrenispredominantlybased ongeneticorinbornerrors,contrarytoadultheartfailure,whichis oftenacquired[130].Asmallnumberofmetabolomicstudieshas beenconductedinthepaediatricpopulation,coveringavarietyof underlying (non-cardiac) diagnoses. In these studies, different metabolicprofileswereidentified inboth healthyand diseased children,therebyofferingtheopportunitytoidentifybiomarkers thathaveadiagnosticortherapeuticvalue[131–140].

Tothebestofourknowledge,nopaediatricmetabolomicstudies have yetbeen conductedin patientson ACE inhibitortherapy. Unfortunately, adult findingscannot simply be extrapolated to childrenformultiplereasons.First,humanserummetabolicprofiles are age-dependent[141].Second,paediatricheart failurediffersfrom adult heart failure in manyrespects, includingprevalence, aetiology, clinicalmanifestationandcomorbidities.Third,maturationofthe RAASoccurs inthe first yearsoflife, making the effectof ACE inhibitortherapymorecomplexandtheextrapolationofdatamore pronetoerrors.Therefore,themetabolomicprofileofchildrenon ACEinhibitortherapywarrantsfurtherstudy.

Concluding

remarks

Inconclusion,amajorinformationgapremainsonthePKandPD ofenalaprilinchildren,especiallyintheyoungestagegroups,as wellasfortheindicationheartfailure.Toofferchildren evidence-basedenalapriltherapy,furtherstudiesareneededtoaddressthese information gaps,includingPKandPD studiessuchasthe EU-fundedLENAproject[11,118].

Reviews

KEYNO

TE

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Declaration

of

competiting

interests

Theauthorsdeclarethattheyhavenoknowncompetingfinancial interestsorpersonalrelationshipsthatcouldhaveappearedto influencetheworkreportedinthispaper.

Acknowledgements

Theresearchleadingtotheseresultshasreceivedfundingfrom EuropeanUnionSeventhFrameworkProgramme(FP7/2007– 2013)undergrantagreementn602295(LENA).

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