中国成年肝移植患者霉酚酸群体药物动力学研究.docx
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中国成年肝移植患者霉酚酸群体药物动力学研究.docx
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中国成年肝移植患者霉酚酸群体药物动力学研究
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中国成年肝移植患者霉酚酸群体药物动力学研究
余自成1,3,陈皓2,FrançoiseBressolle3,张伟霞1,彭承宏1,陈红专3
(1.上海交通大学医学院附属瑞金医院药剂科,上海200025;2.上海交通大学医学院附属瑞金医院器官移植中心,上海200025;3.LaboratoiredePharmacocinétiqueClinique,FacultédePharmacie,UniversitéMontpellierI,Montpellier34093,France;3.上海交通大学医学院药理学教研室,上海200025)
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,包括患者人口统计资料(年龄,性别,体重等),移植术后时间,MMF治疗用药时间,实验室检查结果(血常规,生化检查等),MMF用药剂量,合用的他克莫司剂量和浓度,合用的皮质激素和免疫诱导剂(达珠单抗和巴利昔单抗)等。
将所有72例患者资料用数据分割法(Datasplitting)分成两部分,一部分资料用于建立模型(n=48),另一部分资料用于模型验证(n=24)。
利用NONMEM软件进行群体药动学数据分析,考虑药动学参数随时的变异(Interoccasionvariability,IOV)。
结果:
MPA药动学符合双室一级吸收(无时滞)模型。
血红蛋白水平(Hb)与MPA表观清除率(CL/F)呈正相关,但没有变异因素能够解释表观分布容积(V1/F)的个体间变异。
估算的MPA群体药动学参数分别为CL/F24.0L·h-1,V1/F59.5L,中央室向外周室转运速度常数(k12)0.407h-1,外周室向中央室转运速度常数(k21)0.022h-1,吸收速度常数(ka)0.752h-1,上述参数的个体间变异分别为44.0,56.3,61.4,36.5,and26.9%。
残余随机误差为1.50mg·L-1,IOV为27.5%。
考虑Hb与CL/F的相关关系,利用sigmoidalEmax模型进行药动学-药效学分析。
根据个体一级药动学参数(Bayesian估算值)计算得到平均室间清除率(Q)和外周室分布容积(V2)分别为23.7l/h和16.4L/kg,。
结论:
本文在国内外首次报道了MPA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够很好地描述MPA在中国成年肝移植患者的群体药动学特征以及CL/F与贫血的关系。
这些资料对于MMF在成年肝移植患者的个体化用药具有重要的应用价值。
关键词:
霉酚酸酯;霉酚酸;群体药动学;肝移植;个体化用药
Populationpharmacokineticsofmycophenolicacidinadultlivertransplantrecipients
YuZicheng1,ChenHao2,FrançoiseBressolle3,ZhangWeixia1,PengChenghong2andChenHongzhuan1
(1DepartmentofPharmacology,InstituteofClinicalPharmacology,RuijinHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,P.R.China;2OrganTransplantationCenter,RuijinHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,P.R.China;3LaboratoiredePharmacocinétiqueClinique,FacultédePharmacie,UniversitéMontpellierI,Montpellier,France)
Abstract
Background:
Mycophenolatemofetil(MMF)isincreasinglyusedinlivertransplantationandplaysanimportantroleintheimmunosuppressiveregimeninlivertransplantation.Largeintraindividualandinterindividualvariabilityinthepharmacokineticsofmycophenolicacid(MPA)followingoraladministrationofMMFhasbeenfoundinlivertransplantpatients,thiswidevariabilitysuggestsaneedfortherapeuticdrugmonitoringofMMF.
Objectives:
TheaimofthestudywastodevelopapopulationpharmacokineticmodelforMPAfollowingoraladministrationofMMFinadultlivertransplantrecipientsandtoidentifyfactorsthatexplainMPApharmacokineticvariability.
Patientsandmethods:
PharmacokineticdataforMPAandcovariateinformationwerecollectedretrospectivelyfrom72adultlivertransplantpatients.MPAbloodconcentrationsweremeasuredbyhighperformanceliquidchromatography.Datasplittingwasusedtocreatemodel-buildingandmodel-validationdatasets.PopulationpharmacokineticdataanalysiswasperformedusingtheNONMEMsoftware.Theinteroccasionvariabilitywastakenintoaccountinthemodel.Factorsscreenedforinfluenceonapparentclearance(CL/F)andapparentinitialvolumeofdistribution(V1/F)wereage,gender,bodyweight,liverfunctiontests,albumin,creatinine,uricacid,bloodroutinetests,tacrolimusdose,tacrolimusconcentration,concurrentcorticosteroidsandimmuneinducers(daclizumabandbasiliximab).
Results:
ThepharmacokineticsofMPAwasbestdescribedbyatwo-compartmentmodelwithafirst-orderabsorptionratewithoutalagtime.CovariateanalysisshowedthathemoglobinlevelwaspositivelycorrelatedwithCL/F,butnocovariatesignificantlyexplainedtheinterindividualvariabilityinV1/F.Theestimatedpopulationpharmacokineticparameterswereasfollows:
CL/F24.0L/h,V1/F59.5L,transferrateconstantfromcentralcompartmenttotissuecompartment(k12)0.407hour-1,transferrateconstantfromtissuecompartmenttocentralcompartment(k21)0.022hour-1,andabsorptionrateconstant(ka)0.752hour-1.Theinteroccasionvariabilitywas27.5%.Markedinterindividualvariabilityinpharmacokineticparameters(44.0,56.3,61.4,36.5,and26.9%forCL/F,V1/F,k12,k21andka,respectively)andaresidualrandomerrorof1.50mg/Lwereobserved.TotakeintoaccounttherelationshipbetweenHblevelandCL/Fapharmacokinetic/pharmacodynamicanalysiswascarriedoutusingthesigmoidalEmaxmodel.Themeanintercompartmentclearance(Q)andperipheralvolumeofdistribution(V2)calculatedfromtheindividual(Bayesianestimates)primarypharmacokineticparameterswere23.7l/hand16.4L/kg,respectively.
Conclusion:
ThispaperreportsforthefirsttimepopulationpharmacokineticdataforMPAinadultlivertransplantpatients.TheperformedpopulationanalysisadequatelydescribesthepharmacokineticsofMPAandtherelationshipbetweenCL/Fandanemiainthistransplantpopulation.ThesepopulationpharmacokineticdatahavesignificantclinicalvaluesfortheindividualizationofMMFtherapyinadultlivertransplantpatients.
Text
Background
Mycophenolatemofetil(MMF)istheesterprodrugoftheimmunosuppressantagentmycophenolicacid(MPA),whichactsasaspecificinhibitorofhumanlymphocyteproliferationbyinhibitinginosinemonophosphatedehydrogenase(IMPDH),thekeyenzymeinthedenovopurinebiosynthesisofproliferatingT-andB-lymphocytesandprovideseffectiveimmunosuppressionintransplantpatients.[1]MMFhasbeenwidelyusedintheimmunosuppressiveregimenswithcorticosteroidsandcalcineurininhibitors(CNIs)toreducetheincidenceofacuterejectioninrenaltransplantpatientsanditsefficacyhasbeenconfirmedinseveralrandomizeddouble-blindmulticenterclinicaltrials.[2-5]Inrecentyears,MMFhasbeenincreasinglyusedinlivertransplantationandplaysacentralroleintheimmunosuppressiveregimeninlivertransplantation.[6]MMFhasbeenshowntobeapotentandsafeimmunosuppressantinliverrecipientsforpreventionandtreatmentofacuteorchronicrejection,aswellaschronicgraftdysfunction,andhelpstolowertheserioustoxicsideeffectsofCNIs.[7-10]Moreover,MMFhastheimmunosuppressivepotentialforrescuetherapyafterorthotopiclivertransplantation(OLT).[11]
SomestudieshaveevaluatedthepharmacokineticsofMPAinadultlivertransplantpatients,[12-16]butallofthemhaveusedconventionalnon-compartmentalapproachtocalculatepharmacokineticparameters,withmultipleconcentration-timemeasurementstakenoverasingledosingintervalorarelativelyshorttimeperiod.Thesestudieshavebeencarriedoutinrelativelysmallhomogeneouspatientgroups,intheimmediatepost-transplantperiod.Differentfactorsthatmayalterdrugpharmacokineticshavenotbeeninvestigatedsimultaneously.Suchstudiesprovidelittleinformationoninter-individualandintra-individualpharmacokineticvariability.
TheassociationbetweenMPApharmacokineticsandclinicalefficacyandside-effectshasbeenestablishedinrenal,cardiacandhematopoieticcelltransplantpatients.ManystudieshaveshownthatthereexistsasignificantrelationshipbetweenMPAareaundertheplasmaconcentration–timecurve(AUC)andclinicalresults.[17-23]AlthoughtherelationshipbetweenMPApharmacokineticsandMMFsafetyorefficacyhasnotbeenfullyestablishedinlivertransplantpatients,twostudieshavealreadybeenperformedtomakethisevaluation.OnestudyshowedthatMPApredoselevelmonitoringisclinicallyeffectiveandatherapeuticrangeof1to3.5mg/Lisapplicableinliverallograftrecipients,[24]whichisinagreementwithpreviousresultsinrenalandcardiactransplantpatients.[25]AnotherstudyshowedthatnorelationshipbetweenMPApharmacokineticsandtheefficacyofMMFcouldbeestablished(onlyonepatientdevelopedrejection),probablyduetotheconcomitantadministrationoftacrolimusanddaclizumabintheseliverrecipients.[14]AlargeintraindividualandinterindividualvariabilityinMPApharmacokineticshasbeenfoundinbothadultandpediatriclivertransplantpatients,[12-16,26]thiswidevariabilitysuggestsaneedfortherapeuticdrugmonitoringofMMF.
Continuousadequateimmunosuppressionisimperativeformaintenanceofthegraft,underimmunosuppressioncanleadtorejectionofthegraftwhereasoverimmunosuppressionmayresultinserioustoxicitiesandinfectionsandincreaseriskoflymphoproliferativedisease.Individualizationofdosageregimentoachievetheoptimalimmunosuppressionwouldbeabletoprolongthesurvivalofgraftandimprovetheprognosisoftransplantpatients.MonitoringMPAAUChasbeenproposedfortheindividualizationofMMFtherapyinviewoftherelationshipbetweenMPAAUCandclinicalresults.However,measuring12-hMPAAUCsisimpracticalintheclinicalsetting.Somathematicalequationsbasedonstepwiselinearregressionanalysis(MLR)havebeenproposedtoestimateMPAAUC;theserequiredthreeorfoursamples.[27-33]MLRmodelrequiresaccuratecontrolofthetimeatwhichthesamplesareobtained.Incontrast,Bayesianestimationmethodallowingtheuseofnon-rigidtimesismoreflexibleandusefultoindividualizedosagetoreachspecifictargetconcentrationsorAUCsforeachtransplantrecipient.[34]However,thisapproachrequiresinitialpopulationpharmacokineticinformationonMPA.Recently,LeGuellecetal.[35]andShumetal.[36]reportedpopulationpharmacokineticdataforMPAinadultkidneytransplantpatientstoquantifytheaveragepopulationpharmacokineticparameters,theinterpatientvariabilityandtheinfluence
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- 关 键 词:
- 中国 成年 移植 患者 霉酚酸 群体 药物 动力学 研究