[生物医药论文精品]中国成年肝移植患者霉酚酸群体药物动力学研究

1中国成年肝移植患者霉酚酸群体药物动力学研究中文摘要背景霉酚酸酯（MYCOPHENOLATEMOFETIL，MMF）是一种较新的免疫抑制药物，该药物为前体药物，口服给药后在体内快速地转换成其活性产物霉酚酸（MYCOPHENOLICACID，MPA）。MMF在肝移植的应用日趋广泛，是肝移植免疫抑制方案中的重要药物。肝移植患者口服MMF后MPA药动学在患者个体间和个体内存在较大幅度的变异，提示需要对MMF进行治疗药物监测。目的本项研究的主要目标是建立MPA在中国成年肝移植患者的群体药动学模型，估算MPA的群体药动学参数，定量评估MPA药动学参数在患者个体间及个体内的变异性，鉴别导致MPA药动学变异的可能因素，为MMF临床个体化用药提供科学依据。方法回顾性地收集72例成年肝移植患者的MPA药动学资料及有关临床资料，包括患者人口统G16757资料（年G21848，性别，体重G12573），移植G7427后G7114间，MMF治疗用药G7114间，G4466G20576G4472G7828G7609G13479G7536（G15892G5132G16280，G10995化G7828G7609G12573），MMF用药G2070量，G2524用的G1194G1823G14719G2508G2070量和G8999度，G2524用的G11394G17148G9620素和免疫G16837导G2070（G17810G10676G2345G6251和G5064G2045G7144G2345G6251）G12573。G4570G6164有72例患者资料用数据G2010G2118G8873（DATASPLITTING）G2010成G1016G18108G2010，一G18108G2010资料用G1122建立模型（N48），G2490一G18108G2010资料用G1122模型G20576G16789N24。G2045用NONMEMG17731G1226进行群体药动学数据G2010G7524，G13783G15397药动学参数G19555G7114的变异INTEROCCASIONVARIABILITY,IOV。结果MPA药动学G12538G2524G2464G4472一G13435G2572收（G7092G7114G9394）模型。G15892G13430G15519G11345G8712G5191（HB）G994MPAG15932G16278G9177G19512G10587（CL/F）G2588G8503G11468关，G1306G8821有变异因素能G3827G16311G18334G15932G16278G2010G5079G4493G12227（V1/F）的个体间变异。估算的MPA群体药动学参数G2010别为CL/F240LH1，V1/F595L，中G3842G4472G2533G3818G2620G4472转G17828速度G5132数K120407H1，G3818G2620G4472G2533中G3842G4472转G17828速度G5132数K210022H1，G2572收速度G5132数KA0752H1，G990G17860参数的个体间变异G2010别为440,563,614,365,AND269。G8543G1325G19555G7438G16835G5058为150MGL1，IOV为275。G13783G15397HBG994CL/F的G11468关关G13007，G2045用SIGMOIDALEMAX模型进行药动学G713药G6940学G2010G7524。G7693据个体一G13435药动学参数（BAYESIAN估算G1552）G16757算G5483G2052G5191G3355G4472间G9177G19512G10587（Q）和G3818G2620G4472G2010G5079G4493G12227（V2）G2010别为237L/H和164L/KG,。结论本G7003在国内G3818G20330G8437G6265G17959G1114MPA在成年肝移植患者的群体药动学数据，研究建立的群体药动学模型能G3827G5468G3921地G6563G17860MPA在中国成年肝移植患者的群体药动学G10317G5461G1209及CL/FG994G17151G15892的关G13007。G17837G1135资料对G1122MMF在成年肝移植患者的个体化用药G1867有重要的应用G1227G1552。关键词霉酚酸酯G727霉酚酸G727群体药动学G727肝移植G727个体化用药2POPULATIONPHARMACOKINETICSOFMYCOPHENOLICACIDINADULTLIVERTRANSPLANTRECIPIENTSABSTRACTBACKGROUNDMYCOPHENOLATEMOFETILMMFISINCREASINGLYUSEDINLIVERTRANSPLANTATIONANDPLAYSANIMPORTANTROLEINTHEIMMUNOSUPPRESSIVEREGIMENINLIVERTRANSPLANTATIONLARGEINTRAINDIVIDUALANDINTERINDIVIDUALVARIABILITYINTHEPHARMACOKINETICSOFMYCOPHENOLICACIDMPAFOLLOWINGORALADMINISTRATIONOFMMFHASBEENFOUNDINLIVERTRANSPLANTPATIENTS,THISWIDEVARIABILITYSUGGESTSANEEDFORTHERAPEUTICDRUGMONITORINGOFMMFOBJECTIVESTHEAIMOFTHESTUDYWASTODEVELOPAPOPULATIONPHARMACOKINETICMODELFORMPAFOLLOWINGORALADMINISTRATIONOFMMFINADULTLIVERTRANSPLANTRECIPIENTSANDTOIDENTIFYFACTORSTHATEXPLAINMPAPHARMACOKINETICVARIABILITYPATIENTSANDMETHODSPHARMACOKINETICDATAFORMPAANDCOVARIATEINFORMATIONWERECOLLECTEDRETROSPECTIVELYFROM72ADULTLIVERTRANSPLANTPATIENTSMPABLOODCONCENTRATIONSWEREMEASUREDBYHIGHPERFORMANCELIQUIDCHROMATOGRAPHYDATASPLITTINGWASUSEDTOCREATEMODELBUILDINGANDMODELVALIDATIONDATASETSPOPULATIONPHARMACOKINETICDATAANALYSISWASPERFORMEDUSINGTHENONMEMSOFTWARETHEINTEROCCASIONVARIABILITYWASTAKENINTOACCOUNTINTHEMODELFACTORSSCREENEDFORINFLUENCEONAPPARENTCLEARANCECL/FANDAPPARENTINITIALVOLUMEOFDISTRIBUTIONV1/FWEREAGE,GENDER,BODYWEIGHT,LIVERFUNCTIONTESTS,ALBUMIN,CREATININE,URICACID,BLOODROUTINETESTS,TACROLIMUSDOSE,TACROLIMUSCONCENTRATION,CONCURRENTCORTICOSTEROIDSANDIMMUNEINDUCERSDACLIZUMABANDBASILIXIMABRESULTSTHEPHARMACOKINETICSOFMPAWASBESTDESCRIBEDBYATWOCOMPARTMENTMODELWITHAFIRSTORDERABSORPTIONRATEWITHOUTALAGTIMECOVARIATEANALYSISSHOWEDTHATHEMOGLOBINLEVELWASPOSITIVELYCORRELATEDWITHCL/F,BUTNOCOVARIATESIGNIFICANTLYEXPLAINEDTHEINTERINDIVIDUALVARIABILITYINV1/FTHEESTIMATEDPOPULATIONPHARMACOKINETICPARAMETERSWEREASFOLLOWSCL/F240L/H,V1/F595L,TRANSFERRATECONSTANTFROMCENTRALCOMPARTMENTTOTISSUECOMPARTMENTK120407HOUR1,TRANSFERRATECONSTANTFROMTISSUECOMPARTMENTTOCENTRALCOMPARTMENTK210022HOUR1,ANDABSORPTIONRATECONSTANTKA0752HOUR1THEINTEROCCASIONVARIABILITYWAS275MARKEDINTERINDIVIDUALVARIABILITYINPHARMACOKINETIC3PARAMETERS440,563,614,365,AND269FORCL/F,V1/F,K12,K21ANDKA,RESPECTIVELYANDARESIDUALRANDOMERROROF150MG/LWEREOBSERVEDTOTAKEINTOACCOUNTTHERELATIONSHIPBETWEENHBLEVELANDCL/FAPHARMACOKINETIC/PHARMACODYNAMICANALYSISWASCARRIEDOUTUSINGTHESIGMOIDALEMAXMODELTHEMEANINTERCOMPARTMENTCLEARANCEQANDPERIPHERALVOLUMEOFDISTRIBUTIONV2CALCULATEDFROMTHEINDIVIDUALBAYESIANESTIMATESPRIMARYPHARMACOKINETICPARAMETERSWERE237L/HAND164L/KG,RESPECTIVELYCONCLUSIONTHISPAPERREPORTSFORTHEFIRSTTIMEPOPULATIONPHARMACOKINETICDATAFORMPAINADULTLIVERTRANSPLANTPATIENTSTHEPERFORMEDPOPULATIONANALYSISADEQUATELYDESCRIBESTHEPHARMACOKINETICSOFMPAANDTHERELATIONSHIPBETWEENCL/FANDANEMIAINTHISTRANSPLANTPOPULATIONTHESEPOPULATIONPHARMACOKINETICDATAHAVESIGNIFICANTCLINICALVALUESFORTHEINDIVIDUALIZATIONOFMMFTHERAPYINADULTLIVERTRANSPLANTPATIENTS4TEXTBACKGROUNDMYCOPHENOLATEMOFETILMMFISTHEESTERPRODRUGOFTHEIMMUNOSUPPRESSANTAGENTMYCOPHENOLICACIDMPA,WHICHACTSASASPECIFICINHIBITOROFHUMANLYMPHOCYTEPROLIFERATIONBYINHIBITINGINOSINEMONOPHOSPHATEDEHYDROGENASEIMPDH,THEKEYENZYMEINTHEDENOVOPURINEBIOSYNTHESISOFPROLIFERATINGTANDBLYMPHOCYTESANDPROVIDESEFFECTIVEIMMUNOSUPPRESSIONINTRANSPLANTPATIENTS1MMFHASBEENWIDELYUSEDINTHEIMMUNOSUPPRESSIVEREGIMENSWITHCORTICOSTEROIDSANDCALCINEURININHIBITORSCNISTOREDUCETHEINCIDENCEOFACUTEREJECTIONINRENALTRANSPLANTPATIENTSANDITSEFFICACYHASBEENCONFIRMEDINSEVERALRANDOMIZEDDOUBLEBLINDMULTICENTERCLINICALTRIALS25INRECENTYEARS,MMFHASBEENINCREASINGLYUSEDINLIVERTRANSPLANTATIONANDPLAYSACENTRALROLEINTHEIMMUNOSUPPRESSIVEREGIMENINLIVERTRANSPLANTATION6MMFHASBEENSHOWNTOBEAPOTENTANDSAFEIMMUNOSUPPRESSANTINLIVERRECIPIENTSFORPREVENTIONANDTREATMENTOFACUTEORCHRONICREJECTION,ASWELLASCHRONICGRAFTDYSFUNCTION,ANDHELPSTOLOWERTHESERIOUSTOXICSIDEEFFECTSOFCNIS710MOREOVER,MMFHASTHEIMMUNOSUPPRESSIVEPOTENTIALFORRESCUETHERAPYAFTERORTHOTOPICLIVERTRANSPLANTATIONOLT11SOMESTUDIESHAVEEVALUATEDTHEPHARMACOKINETICSOFMPAINADULTLIVERTRANSPLANTPATIENTS,1216BUTALLOFTHEMHAVEUSEDCONVENTIONALNONCOMPARTMENTALAPPROACHTOCALCULATEPHARMACOKINETICPARAMETERS,WITHMULTIPLECONCENTRATIONTIMEMEASUREMENTSTAKENOVERASINGLEDOSINGINTERVALORARELATIVELYSHORTTIMEPERIODTHESESTUDIESHAVEBEENCARRIEDOUTINRELATIVELYSMALLHOMOGENEOUSPATIENTGROUPS,INTHEIMMEDIATEPOSTTRANSPLANTPERIODDIFFERENTFACTORSTHATMAYALTERDRUGPHARMACOKINETICSHAVENOTBEENINVESTIGATEDSIMULTANEOUSLYSUCHSTUDIESPROVIDELITTLEINFORMATIONONINTERINDIVIDUALANDINTRAINDIVIDUALPHARMACOKINETICVARIABILITYTHEASSOCIATIONBETWEENMPAPHARMACOKINETICSANDCLINICALEFFICACYANDSIDEEFFECTSHASBEENESTABLISHEDINRENAL,CARDIACANDHEMATOPOIETICCELLTRANSPLANTPATIENTSMANYSTUDIESHAVESHOWNTHATTHEREEXISTSASIGNIFICANTRELATIONSHIPBETWEENMPAAREAUNDERTHEPLASMACONCENTRATIONTIMECURVEAUCANDCLINICALRESULTS1723ALTHOUGHTHERELATIONSHIPBETWEENMPAPHARMACOKINETICSANDMMFSAFETYOREFFICACYHASNOTBEENFULLYESTABLISHEDINLIVERTRANSPLANTPATIENTS,TWOSTUDIESHAVEALREADYBEENPERFORMEDTOMAKETHISEVALUATIONONESTUDYSHOWEDTHATMPAPREDOSELEVELMONITORINGISCLINICALLYEFFECTIVEANDATHERAPEUTICRANGEOF1TO35MG/LISAPPLICABLEINLIVERALLOGRAFTRECIPIENTS,24WHICHISINAGREEMENT5WITHPREVIOUSRESULTSINRENALANDCARDIACTRANSPLANTPATIENTS25ANOTHERSTUDYSHOWEDTHATNORELATIONSHIPBETWEENMPAPHARMACOKINETICSANDTHEEFFICACYOFMMFCOULDBEESTABLISHEDONLYONEPATIENTDEVELOPEDREJECTION,PROBABLYDUETOTHECONCOMITANTADMINISTRATIONOFTACROLIMUSANDDACLIZUMABINTHESELIVERRECIPIENTS14ALARGEINTRAINDIVIDUALANDINTERINDIVIDUALVARIABILITYINMPAPHARMACOKINETICSHASBEENFOUNDINBOTHADULTANDPEDIATRICLIVERTRANSPLANTPATIENTS,1216,26THISWIDEVARIABILITYSUGGESTSANEEDFORTHERAPEUTICDRUGMONITORINGOFMMFCONTINUOUSADEQUATEIMMUNOSUPPRESSIONISIMPERATIVEFORMAINTENANCEOFTHEGRAFT,UNDERIMMUNOSUPPRESSIONCANLEADTOREJECTIONOFTHEGRAFTWHEREASOVERIMMUNOSUPPRESSIONMAYRESULTINSERIOUSTOXICITIESANDINFECTIONSANDINCREASERISKOFLYMPHOPROLIFERATIVEDISEASEINDIVIDUALIZATIONOFDOSAGEREGIMENTOACHIEVETHEOPTIMALIMMUNOSUPPRESSIONWOULDBEABLETOPROLONGTHESURVIVALOFGRAFTANDIMPROVETHEPROGNOSISOFTRANSPLANTPATIENTSMONITORINGMPAAUCHASBEENPROPOSEDFORTHEINDIVIDUALIZATIONOFMMFTHERAPYINVIEWOFTHERELATIONSHIPBETWEENMPAAUCANDCLINICALRESULTSHOWEVER,MEASURING12HMPAAUCSISIMPRACTICALINTHECLINICALSETTINGSOMATHEMATICALEQUATIONSBASEDONSTEPWISELINEARREGRESSIONANALYSISMLRHAVEBEENPROPOSEDTOESTIMATEMPAAUCTHESEREQUIREDTHREEORFOURSAMPLES2733MLRMODELREQUIRESACCURATECONTROLOFTHETIMEATWHICHTHESAMPLESAREOBTAINEDINCONTRAST,BAYESIANESTIMATIONMETHODALLOWINGTHEUSEOFNONRIGIDTIMESISMOREFLEXIBLEANDUSEFULTOINDIVIDUALIZEDOSAGETOREACHSPECIFICTARGETCONCENTRATIONSORAUCSFOREACHTRANSPLANTRECIPIENT34HOWEVER,THISAPPROACHREQUIRESINITIALPOPULATIONPHARMACOKINETICINFORMATIONONMPARECENTLY,LEGUELLECETAL35ANDSHUMETAL36REPORTEDPOPULATIONPHARMACOKINETICDATAFORMPAINADULTKIDNEYTRANSPLANTPATIENTSTOQUANTIFYTHEAVERAGEPOPULATIONPHARMACOKINETICPARAMETERS,THEINTERPATIENTVARIABILITYANDTHEINFLUENCEOFCOVARIATESONTHEPARAMETERSTODATE,NOINFORMATIONONTHEPOPULATIONPHARMACOKINETICSOFMPAINLIVERTRANSPLANTRECIPIENTSHASBEENPUBLISHEDTHEPURPOSEOFTHISSTUDYWASITODETERMINEACCURATEPOPULATIONPHARMACOKINETICPARAMETERSOFMPAINADULTLIVERTRANSPLANTRECIPIENTS,IITOACCURATELYESTIMATEBOTHINTERANDINTRAINDIVIDUALVARIABILITYINPHARMACOKINETICPARAMETERSIIITOESTIMATETHEINTEROCCASIONVARIABILITY,ANDIVTOIDENTIFYFACTORSCOVARIATESTHATEXPLAINPHARMACOKINETICVARIABILITYINTHISPOPULATIONPATIENTSANDMETHODSPATIENTSANDDATACOLLECTION6DATAWERECOLLECTEDFROM72ADULTLIVERTRANSPLANTPATIENTS63MALES,9FEMALESWHOHADUNDERGONELIVERTRANSPLANTATIONATORGANTRANSPLANTATIONCENTERINRUIJINHOSPITAL,SHANGHAIJIAOTONGUNIVERSITYSCHOOLOFMEDICINE,SHANGHAI,PRCHINATHEINVESTIGATIONALPROTOCOLWASAPPROVEDBYTHEREGIONALETHICSCOMMITTEERUIJINHOSPITAL,SHANGHAIJIAOTONGUNIVERSITYSCHOOLOFMEDICINEANDPERFORMEDINACCORDANCEWITHTHELEGALREQUIREMENTS,WITHTHEDECLARATIONOFHELSINKIOF1975ASREVISEDIN1983,ANDWITHCURRENTCHINESEGUIDELINESFORGOODCLINICALPRACTICEALLTHEPATIENTSGAVEINFORMEDCONSENTBEFOREINCLUSIONPHARMACOKINETIC,DEMOGRAPHIC,ANDCOVARIATEDATAWERECOLLECTEDRETROSPECTIVELYFROMPATIENTMEDICALRECORDSANDATHERAPEUTICDRUGMONITORINGDATABASEFORALLPATIENTS,APHYSICALEXAMINATION,ANDSTANDARDLABORATORYANALYSES,INCLUDINGHEMATOLOGICALANDBIOCHEMICALTESTS,WEREPERFORMEDDURINGTHESTUDYPERIODDURINGTREATMENT,ONE72PATIENTS,TWO62PATIENTS,THREE33PATIENTSORFOUR5PATIENTSCONCENTRATIONTIMEPROFILEWEREOBTAINEDFOREACHPATIENTTOACCURATELYADJU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