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PHARMACOGENETICSIn-WhaKim&YooJinMoon&EunheeJi&KyungImKim&NayoungHan&SungJuKim&WanGyoonShin&JongwonHa&Jeong-HyunYoon&HyeSukLee&JungMiOhReceived:17October2011/Accepted:21November2011/Publishedonline:20December2011#Springer-Verlag2011AbstractPurposeThepurposeofthisstudywastocharacterizetheeffectsofclinicalandgeneticvariablesonthepharmacoki-neticsandcomplicationsoftacrolimusduringthefirstyearafterkidneytransplantation.
MethodsOnehundredandthirty-twoKoreankidneyrecip-ientswhoreceivedtacrolimusweregenotypedforABCB1(exons12,21,and26)andCYP3A5(intron3).
Tacrolimustroughlevels,dose,ordose-adjustedtroughlevelsandcom-plicationswerecomparedamongpatientsduringtheearlystage(3,7,14,30,and90days)andupto1yearaccordingtothegenotypes.
ResultsAdonorsource-adjustedlinearmixedmodelwithmultilevelanalysisadjustingforage,bodyweight,hemato-crit,andserumcreatinineshowedthatCYP3A5genotypeisassociatedwithdose-adjustedleveloftacrolimus(pT),exon21(2677G>T/A),andexon26(3435C>T).
Thenon-synonymousSNPG2677T>A,andthesynonymousSNPC3435ThavebeenreportedtobecorrelatedwithcellularexpressionlevelsofABCB1[17]andthusmayinfluencethetacrolimuspharma-cokinetics.
However,theeffectoftheseABCB1polymor-phismsontacrolimuspharmacokineticsandclinicaloutcomesstillremainscontroversial[15,18–23]Moreover,littleisknownabouttheassociationofCYP3A5andABCB1genotypeswithtacrolimuspharmacokinetics,especiallywhenstratifiedbydonorsourcesintheearlystageoftrans-plantation.
Tostudytheseassociationswiththerepeatedmeasurementsoftacrolimusthatarelikelypositivelycorre-latedovertime,aflexibleyetversatilemodel,likealinearmixedeffect(LME)modelshouldbeusedfortheanalysis.
Likewise,whenanalysisofthefactorsassociatedwiththeclinicaloutcomesoftacrolimusthataretransientovertimeandcanbecorrelatedwithmanydifferentfactors,aregres-sionmodelsuchasthegeneralizedestimatingequation(GEE)modelisappropriatetoproduceefficientandunbi-asedregressionestimates.
Accordingly,thepurposeofthisstudywastoexplicatethelinearmixedeffectsmodelandGEEmodelasameansoftestingthefactorsthataccountfortheindividualvariationsinthepharmacokineticsandthecomplicationsoftacrolimusduringtheearlystage(3,17,14,30,and90days)andupto1yearaftertransplantationinKoreankidneytransplantrecipients.
MaterialsandmethodsPatientsDatafrom132renalallograftrecipientswhoreceivedkid-neytransplantationfromSeoulNationalUniversityHospi-tal,Seoul,Koreabetween2002and2008werereviewedretrospectively.
Patientsaged>18years,andsingleprimaryorsecondarykidneyrecipientspluscombinedorgantrans-plantationswereeligible.
TheinstitutionalreviewboardoftheClinicalResearchInstituteatSeoulNationalUniversityHospitalapprovedthestudyprotocol(IRBNo.
C-0609-014-182).
Writteninformedconsentwasobtainedfromallsub-jectsbeforebeingenrolledinthisstudy.
ImmunosuppressiveprotocolanddatacollectionAninitialoraldoseof0.
075–0.
1mg/kgtacrolimuswasadministeredtwicedailythedaybeforetransplantationforcadavericdonororgansrecipients,and2hbeforetransplan-tationinthecaseoflivinggrafts,whichwasthenadjustedaccordinglytothetacrolimustherapeuticdrugmonitoring(TDM).
Thedoseoftacrolimuswasadjustedtomaintainthetargetbloodtroughconcentrationof10–12ng/mLduringthefirstmonth.
Theconsequentwhole-bloodtargettroughconcentrationswereadjustedto15–20ng/mLduringthefirst5days,8–12ng/mLupto3months,6–8ng/mLupto6months,and4–6ng/mLthereafter.
Thesteroidswasgivenatastandardintravenousdoseof500mgmethylpredniso-loneatthetimeofsurgery,andwasthenwasgraduallytaperedtoamaintenancedoseof10mgby2weeksaftertransplantation.
Mycophenolatemofetil(MMF)wasadmin-isteredorallyatafixeddoseof1–1.
5g/day.
SomeofthepatientswhoreceivedMMFexperiencedgastrointestinaldisorders,whichledtoachangeintherapytoenteric-coatedmycophenolatesodium.
Otherconcomitantmedica-tionswerescreenedforpossibleCYP3A5andABCB1inter-actions.
Recipientswithcadavericdonorkidneys,positiveresultsonapanelreactiveantibodytest,and/orwhohadmorethanthreemismatchesofhumanleukocyteantigens,wereadministeredtwodoses(20mgeach)ofIVbasilix-imab(Novartis,EastHanover,NJ,USA)1hpreoperativelyandonday4aftertransplantation.
658EurJClinPharmacol(2012)68:657–669TacrolimusmeasurementsTacrolimustroughsamplesweretakenapproximately12hafterthelastdoseondays3,7,14,30,90,180,and360.
Whole-bloodtacrolimusconcentrationsweredeterminedusingamicroparticulateenzymeimmunoassay(IMxana-lyzer;TacrolimusII;AbbottDiagnostics,AbbottPark,IL,USA).
Dose-adjustedtroughconcentrationswerecalculatedbydividingtacrolimustroughconcentrationsbythecorresponding24-hdoseonmg/kgbasis.
Clinicalandsafetyfollow-upAtthetimeoftroughlevelsampling,acompletebiochem-icalbloodanalysiswasperformedtomeasurethelevelsofbloodurinenitrogen,serumcreatinine,electrolytes,glucose,hematologyparameters,lipids,andalbumin.
CreatinineclearancewascalculatedusingtheModificationofDietinRenalDiseaseStudyequation[24]andmeasuredfrom24-hurinecollections.
Patientsunderwentacompletephysicalexamination,includingstandardizedmeasurementofsystol-icanddiastolicbloodpressure,bodyweight,andvitalsigns.
Concomitantmedicationwasnotedandtheuseoflipid-loweringdrugs,antihypertensivedrugs,andanti-diabeticdrugsinparticular,wererecordedcarefully.
Allpatientsunderwentprotocolrenaltransplantbiopsiesattransplanta-tionand10daysaftertransplantation,atwhichtimeTDMcanbecomeeffectiveandthetargettacrolimustroughcon-centrationisachieved.
Recipientswith≥20%elevationsofserumcreatininelevelsunderwentultrasound-guidedpercu-taneousallograftbiopsiesonanydayaftertransplantation.
Acuteallograftrejection,calcineurininhibitor(CNI)-in-ducednephrotoxicityandchronicallograftnephropathywereexclusivelydiagnosedbasedonhistologicalfindingsbyanexperiencedrenalhistopathologistaccordingtothe1997Banffclassificationcriteria[25].
Patientswereconsid-eredtohavearterialhypertensionifsystolicand/ordiastolicbloodpressureexceeded140/90mmHgorwereonantihy-pertensivedrugs.
Recipientswereconsideredtohavehyper-lipidemiaifthefastingtotalcholesterollevelexceeded190mg/dL,low-densitylipoproteincholesterollevelwasabove110mg/dL,and/orthepatientswerereceivinganti-triglyceridedrugs.
Newonsetdiabetesmellitusaftertrans-plantation(NODAT)wasconfirmedthroughastandardoralglucosetolerancetestinpatientswithsuspectedhypergly-cemiaandwasdefinedastheuseofanti-diabeticdrugsformorethan6months[26].
IdentificationofgenotypesGenomicDNAwasisolatedfromwholevenousbloodusingtheQIAampDNAbloodkit(Qiagen,Valencia,CA,USA)accordingtothemanufacturer'sprotocol.
GenotypingforCYP3A5(6986A>G)(rs776746)andABCB1exon12(C1236T)(rs1128503)andexon26(C3435T)(rs1045642)SNPswasperformedusingtheTaqManallelicdiscriminationassaywithanABI7900HT(AppliedBio-systems,FosterCity,CA,USA)[23].
Polymerasechainreaction(PCR)wasprogrammedasfollows:95°Cfor15minfollowedby40cyclesat95°Cfor15sand60°Cfor1min.
TheABCB1exon21(G2677T/A)(rs2032582)regionwasamplifiedusingPCR.
PCRwasprogrammedasfollows:94°Cfor5minand40cyclesat94°Cfor30s,48°Cfor30sand72°Cfor1min,followedby72°Cfor7min.
Amplifiedproductswerepurifiedwith1.
2%agarosegelsusingPCRpurification(PCRquick-spin;iNtRONBiotechnol-ogy,Gyeonggi-do,Korea).
Wholesequencesofamplifiedfragmentswerethendetermined[18].
Boththepatientsandtheinvestigatorswereblindedtothepatients'geneticvariants.
PrimersandprobesweredesignedwithPrimerExpressSoftwareVersion3.
0(AppliedBiosystems)andareshowninTable1.
StatisticalanalysesQuantitativedatawererepresentedasfrequenciesandper-centages,whilequalitativedatawerepresentedasmean±standarddeviation.
TheMann–WhitneyUtestandKruskal–Wallistestwereusedtocomparecontinuousvariablesbe-tweengenotypegroupswithposthoctestingformultiplecomparisons.
CategoricalvariableswereanalyzedusingtheChi-squaredtestandFisher'sexacttest.
Weperformedlinearmixedmodelanalysesonrepeatedmeasuresoftacro-limustroughlevels,doses,anddose-adjustedtroughlevels.
Clinicalcovariatesappliedinthemodelwereage,sex,bodyweight,steroidandMMFdoses,hematocrit,serumcreati-nine,albumin,creatinineclearance,andconcomitantmedi-cations.
Linearmixedmodelanalyseswererepeated,adjustingthemeanfordonorsourceusingamultilevelmodelwithadjustmentsfortheaforementionedcovariates.
Analysisofvariancefollowedbymultipleregressionanal-ysiswasusedtoassessthecontributionofcorticosteroiddoseandotherclinicalcovariatestotacrolimustroughlev-els,dose,anddose-adjustedlevelsatdifferenttimepointsaftertransplantation.
Covariateswithapvalueof5%.
Noneofthesesixhaplotypeswasassociatedwithtacrolimusdose-adjustedtroughlevels.
Combinationsofthethreepredominanthap-lotypesshowedthatonlyonepatientcarrieddiplotypeTTT–TTTofABCB1.
TTThaplotypecarriersdisplayedlowertacrolimusdose-adjustedtroughlevelsthannon-TTTcar-riersonday3post-transplantation(p10ng/mLmustbeachieved[31]bydays2–3aftertransplantationtominimizegraftrejections[7].
PolymorphismsinABCB1andCYP3A5areexpectedtoaffectthisinterindividualvariabilityintacrolimuspharma-cokineticsandclinicaloutcomesintheearlystageoftrans-plantation.
Inourpatients,thetacrolimustroughconcentrationonday3variedwidely,rangingfrom6.
27to32.
00ng/mL.
Morespecifically,12patients(9%)hadTable7Univariateandmultivariatecoxproportionalhazardsanalysesforbiopsy-provenacuterejectionsVariablesUnivariateMultivariateHazardratio(95%CI)pvalueHazardratio(95%CI)pvalueMalegender(vsfemale)1.
196(0.
401~3.
579)0.
748––Age1.
052(1.
005~1.
102)0.
0311.
049(0.
999~1.
102)0.
054Bodyweight1.
010(0.
963~1.
059)0.
693––New–onsetdiabetesaftertransplantation(vsnodiabetes)0.
577(0.
181~1.
840)0.
352––Hypertension(vsnohypertension)0.
723(0.
095~5.
524)0.
754––Hyperlipidemia(vsnohyperlipidemia)0.
917(0.
205~4.
098)0.
910––Deceaseddonor(vslivingdonor)3.
250(1.
139~9.
272)0.
0282.
878(1.
007~8.
226)0.
048ABCB11236CA(vsCC)0.
478(0.
114~2.
001)0.
312––TT(vsCC)0.
962(0.
241~3.
848)0.
957––ABCB12677GA/GT(vsGG)0.
665(0.
183~2.
417)0.
536––AA/AT/TT(vsGG)0.
389(0.
040~3.
740)0.
413––ABCB13435CA(vsCC)0.
794(0.
256~2.
461)0.
689––TT(vsCC)1.
637(0.
330~8.
114)0.
546––CYP3A5*1/*3(vs*1/*1)0.
169(0.
011~2.
696)0.
208––*3/*3(vs*1/*1)1.
122(0.
146~8.
627)0.
912––RelativeriskofacuterejectionforeachvariableisgivenasHR(95%CI)andthepvalueforCoxproportionalhazardsanalysiswithcensoringforpatientdeath,graftfailure,andendoffollow-upTable8Associationbetweenclinicalcovariatesandtacrolimus-inducedcomplicationsaComplicationsVariablesUnivariateMultivariateEstimate95%CIpvalueEstimate95%CIpvalueDiabetes(n022)Tacrolimustroughlevel1.
0950.
998~1.
2020.
054–––Tremor(n014)Age1.
0460.
992~1.
1020.
097–––Hairloss(n034)Tacrolimustroughlevel1.
2431.
146~1.
34715μg/mL[39].
Ithasbeenreportedthattacrolimuscanincreasevery-low-densitylipoproteinandhigh-densitylipo-proteincholesterols[40],buttherewasnoreportsofacorrelationbetweendruglevelandserumlipids.
Inauni-variateanalysis,tacrolimustroughlevelswereexpectedtoincreasetheincidenceofNODATwithborderlinesignifi-cance(p00.
054).
OnecanthinkthatgenotypesofCYP3A5andABCB1maybeassociatedwithriskoftacrolimus-relatedcomplications.
However,nostudytodatehassuc-cessfullydemonstratedtheroleofCYP3A5*3orABCB1genotypesintacrolimus-relatedcomplications[16,41].
Hy-perlipidemiaoccurredapproximately3-foldhigherinCYP3A5*3/*3carrierscomparedwithCYP3A5*1carriersafteradjustingtacrolimustroughlevel(p00.
045).
Ofnote,andtoourknowledge,thisisthefirststudytodemonstratethatclinicalandgeneticfactorsareassociatedwithtacrolimuspharmacokineticsandclinicaloutcomesusingstatisticaltoolslikealinearmixedeffectmodelforrepeatedmeasurementsoftacrolimusovertimeandagen-eralizedestimatingequationmodeltoproduceefficientandunbiasedregressionestimates.
WehaveexplicatedthelinearmixedeffectsmodelandGEEmodelasameansoftestingtheassociationamongthecovariates,thepharmacokinetics,andthecomplicationsoftacrolimusduringtheearlystagesEurJClinPharmacol(2012)68:657–669667andupto1yearaftertransplantationinKoreankidneytransplantrecipients.
ThepossiblelimitationofourstudyisthatwecouldnotstudytheeffectsoftheABCB1TTT-TTThaplotypebecauseonlyonerecipientcarriedthisdiplotypeinourstudy.
More-over,wecouldnotfindadefinitiveassociationbetweenthegenepolymorphismofCYP3A5andcomplications,possiblyowingtotheeffortsofmaintainingsimilartroughlevelsoftacrolimuswithTDMamongstrecipientsofdifferentCYP3A5genotypes.
Additionally,theassayweusedforthedeterminationoftacrolimusmeasurementscouldnotdistinguishbetweenactiveandinactivemetabolites.
Anoth-erpossiblelimitationisthatourstudywasaretrospectivestudy.
AprospectivecontrolledstudywithalargernumberoftransplantrecipientsiswarrantedtofurtherconfirmtheclinicalsignificanceofCYP3A5andABCB1genotypesontransplantationoutcomesinpatientstreatedwithtacrolimus.
Inconclusion,age,bodyweight,hematocrit,serumcre-atininelevels,andCYP3A5genotypeswerefoundtobesignificantfactorsresponsibleforaffectingthetacrolimusdose-adjustedtroughlevels.
Additionally,transplantationofacadavericdonorkidneywasassociatedwithincreasedincidenceofacuterejections,whileatacrolimustroughlevelwasasignificantpredictingfactorfortacrolimus-relatedcomplicationsincludingalopeciaandhyperlipidemia.
Theclinicalandgeneticfactorswehaveidentifiedcouldcon-tributetotheindividualizationoftacrolimustreatmentandenhancedrugsafetyandresponse,helpingtoobtainade-quateimmunosuppressionwithoutincreasingtheriskofcomplicationsinkidneytransplantpatients.
AcknowledgementsThisworkwassupportedbyagrantfromtheNationalResearchFoundationofKorea,fundedbytheKoreangovern-mentMinistryofEducation,ScienceandTechnology(no.
2009–0081414)andbyagrantfromtheKoreaHealthtechnologyR&DProject,MinistryofHealth&Welfare,RepublicofKorea(A090930)andtheClinicalResearchInstitute(CRI),SeoulNationalUniversityHospital(no.
1120070027).
ConflictofinterestTheauthorsdeclarenocompetinginterests.
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