侵袭性真菌感染患者伏立康唑群体药动学研究及给药方案优化_王陶陶

81201490*Tel/[e-mail]王陶陶1，孙金钥1，陈思颖1，蔡江霞1，程晓亮2，王雪3，董海燕1，董亚琳1*1.7100612.1001913.ICU710061本实验旨在评价伏立康唑在侵袭性真菌感染患者中的群体药动学特征，寻找影响伏立康唑药动学参数变化的因素，并对给药方案进行优化，以指导临床用药。为定量描述协变量与伏立康唑药动学参数之间的关系，采用了群体药动学的研究方法对侵袭性真菌感染患者的临床稀疏血样进行分析。观察患者人口学资料、生化指标、合并用药、基因型等协变量对药动学参数的影响。使用内部验证Bootstrap法对最终模型进行验证。利用蒙特卡洛模拟法对给药方案进行优化。通过NONMEM(monlinearmixedeffectmodoling)程序对151例住院患者的406个血样进行分析发现，具有一级吸收和一级消除的一房室模型能够很好地拟合这些数据。其中，表观分布容积为200L，清除率为6.95L·h－1。患者年龄、CYP2C19基因型和碱性磷酸酶值对清除率有显著的影响。内部验证结果表明最终模型稳定可靠。在患者人群中，200mg/q12h，iv或200mg/q12h，po的给药方案对曲霉菌感染是有效的。200mg/q12h，iv或300mg/q12h，po的给药方案对治疗念珠菌感染是有效的。蒙特卡洛模拟法与群体药动学参数结合可以指导临床优化给药方案。伏立康唑;群体药动学;NONMEM;侵袭性真菌感染;蒙特卡洛模拟法doi:10.11669/cpj.2014.03.015Ｒ969A1001－2494201403－0227－07PopulationPharmacokineticsStudyofVoriconazoleandDosingＲegimenOptimizationinPatientswithIn-vasiveFungusInfectionsWANGTao-tao1SUNJin-yue1CHENSi-yin1CAIJiang-xia1CHENGXiao-liang2WANGXue3DONGHai-yan1DONGYa-lin1*1.DepartmentofPharmacyTheFirstAffiliatedHospitalofXi'anJiaotongUniversityXi'an710061Chi-na2.DepartmentofPharmaceuticsSchoolofPharmaceuticalSciencesPekingUniversityHealthScienceCenterBeijing100191Chi-na3.CentralIntensiveCareUnitTheFirstAffiliatedHospitalofXi'anJiaotongUniversityXi'an710061ChinaABSTＲACTOBJECTIVETocharacterizethepharmacokineticsofvoriconazolefindthefactorsinfluencingpharmacokineticsandoptimizedosingregimeninpatientswithinvasivefungusinfectionsIFIs．METHODSToprospectivelyquantitatetherelationshipbetweenVＲCparametersandcovariatesapopulationpharmacokineticsanalysiswasconductedonpooleddatafrompatientswithinva-sivefungusinfections.ThelistofcovariatestestedincludeddemographicfactorsbiochemistryconcomitantmedicationsandCYP2C19genotype.Thefinalmodelwasinternallyevaluatedusingbootstrapmethod.MonteCarlosimulationwasusedtoevaluatetheeffectiveofcurrentlyrecommendeddosingregimenandtodesignanoptimizedpharmacodynamicsdosingstrategyforVＲC.ＲESULTSFourhun-dredandsixsamplesfrom151patientswerecollectedforpopulationpharmacokineticsanalysis.Aone-compartmentmodelwithfirst-or-derabsorptionandeliminationasthebasicstructuralmodelappropriatelyfittedthedata.VＲCclearancewas6.95L·h－1volumeofdistributionwas200L.TheclearancewassignificantlyassociationwithagealkalinephosphataseandCYP2C19genotype.Bootstrapmethodconfirmedthatthepharmacokineticsparameterswasaccurateandthefinalmodelwasrobust.MonteCarlosimulationsuggeststhatrecommendeddosingregimenfortreatAspeglliusinfectionsand300mgq12hpoor200mgq12hiv.dripfortreatCandidainfec-tionsareeffective.CONCLUSIONThisstudyisabletoshowthattheoptimalVＲCdosageregimensaresuccessfullydeterminedu-singprospectivepopulationpharmacokineticsanalysisandMonteCarlosimulation.KEYWOＲDSvoriconazolepopulationpharmacokineticsNONMEMinvasivefungusinfectionMonteCarlosimulationvoriconazoleVＲC、、、、·722·20142493ChinPharmJ2014FebruaryVol.49No.31-3。VＲC4-6。VＲC0.2mg·L－112mg·L－17-8。CYP2C19、159-10。MetaVＲC1～4mg·L－111。VＲC、PPK。VＲCⅡ。。/PK/PD12。VＲCPK/PDfAUC/MIC≥2513-14。MonteCarlosimula-tionMCS。OPTAMAPK/PD、15。11.12008120128VＲC151EOＲTC/MSG。、、、。VＲC18。。1.2、AGE、BW、HGB、PLT、ALT、AST、ALP、TBIL、ALB、TP、CＲEA、CLcrCYP2C19UM、EM、IMPMOME、DEX、AZI1。1.3VＲC2mLEDTA3000r·min－15minCYP2C19。HighPer-formanceLiquidChromatographyHPLCVＲC。Waters2996HypersilC18ODS-60∶4080μLpH3.01.0mL·min－1260nm50μL。0.06～8.00mg·L－1r2=0.9998、4.7%7.7%90%。1.4CYP2C19DNADNANanodrop2000cDNAMassAＲＲAY。1.5NONMEMVersionⅦLevel2.0GloboMaxLLCUSAADVAN6。22.1151406NONMEMnonlinearmixedeffectmodelingADVAN6。2.1.1FOCEfirst-orderconditionalestimation、、tlag。CL、Vd·822·ChinPharmJ2014FebruaryVol.49No.320142493F。Ka1.1h－116。2.1.2VＲC。Pij=TVPj*eηijPijijTVPjj。ηijPijTVPj0ω2。Additiveerrormodelcobs=cpred+εProportionalerrormodelcobs=cpred×1+εCombinederrormodelcobs=cpred×1+ε+ε1Exponentialerrormodelcobs=cpred×expεcobscpredε。εε10σ2σ12。2.1.3NONMEMobjectivefunctionvalueOFVmaximumlikeli-hood－2LL。χ2。df=11χ20.051=3.84χ20.0011=10.83。ΔOFV＞3.84ΔOFV＞10.83P＜0.05P＜0.001。①。OFV3.84P＜0.05。OFV。②。ΔOFV＞10.83P＜0.001。①OFV。②ＲSE。③。④。⑤。2.1.4Bootstrap。NONMEMBootstrap100095%。2.2MICprobabilityoftargetattain-mentPTAMICcumulativefractionofresponseCFＲ17CFＲ＞90%18。fAUC24/MIC≥25。fAUC24AUC24=DOSE×F/CL58%fAUC1DOSEmg·d－1CLFF=1CLF。MIC1。100mg/q12h、200mg/q12h300mg/q12h6。33.1151VＲC406。HPLCVＲCVＲC0.11～9.16mg·L－164.0%1～4mg·L－120.2%1mg·L－115.8%4mg·L－1。1。1MICFig.1VＲCsusceptibilityagainstclinicalisolatesofAspegillusandCandidaspices.ThefrequencyofisolatesateachMICisgiven·922·20142493ChinPharmJ2014FebruaryVol.49No.31Tab.1DemographicandclinicaldataParameterValueVoriconazoleserumconcentrationmg·L－12.21±1.760.11－9.16Covariateno.ofpatientsGendermale/female104/47UM∶EM∶IM∶PM3∶64∶65∶19Patientage/years61±2161.018－99Bodyweight/kg59.1±7.860.035－80CovariatesMean±SDmedianrangHGB/g·L－199.9±22.497.052.0－168PLT/109·L－1158.7±113.9133.02.8－641.0AST/U·L－134.6±55.326.01.0－642.0ALP/U·L－142.2±57.8104.26.0－586.0ALT/U·L－1127.2±75.321.02.0－693.0TBIL/mol·L－119.8±41.511.91.7－521.3ALB/g·L－131.1±6.031.11.3－52.4CＲEA/mmol·L－1119.6±95.885.829.9－729.8CLcr1/L·min－166.1±38.755.87.1－242.11Cockroft＆GaultHGB－PLT－AST－ALP－ALT－TBIL－ALB－CＲEA－CLcr－UM－EM－IM－PM－Note1CalculatedwithCockroft＆Gau