抗真菌药物PKPD研究新进展

[e-mail][e-mail]123PK/PDEpidemiologyofsepsisintheUSMartinetal.NEJM(2003)348;1546-1554EpidemiologyofsepsisintheUSMartinetal.NEJM(2003)348;1546-155400225,000225,000150,000150,00075,00075,00025,00025,0005,0005,0001,0001,00015,00015,0007979818183838585898987879191939395959797999920012001No.ofCasesofsepsisNo.ofCasesofsepsis********************************************NumbersofCasesofsepsisintheUnitedStates,AccordingtotheCausativeOrganism,1979-2000NumbersofCasesofsepsisintheUnitedStates,AccordingtotheCausativeOrganism,1979-2000++********************************************++++++++++++++++++++++++++++++++++++++++++zzzzzzzzFUNGIYeastDimorphicfungMoldCryptococcusTrichosporeCandidaHistoplasmaBlastomycasSporothrixCoccidioidesAspergillusZygomytesFusariumDermatophyteTrichophytonMicrosporumEpidermophytonJohnR.Wingard,IDSA,2005764zzzzzz%30.836.520.46.16.2PUMCH%582011722123PK/PD//5--1,3-Caspofunginmicafunginanidulafungin20003caspofungin)CancidasMK-0991Merck&Co.2001micafungin)FunguardFK-4362002anidurafungin)EraxisLY-303366Pfizer/Vicuron20063voliconazoleVfendTMUK-109496Pfizer2002fosfluconazoleProdifUK-292663Pfizer2003posaconazole)NoxafilSCH56592Schering-Plough2005BSSSSSSSSSSSSSSSSSS/17S/S+DDSS/IS/IS/ISS+DD/RS+DD/RS/IS/IS/ISRS+DD/RSSSSSSS/RSSSCuenca-EstrellaM.Antimicrob.AgentsChemother.2006Mar,50:917.AmBFLUITRVORPOS9400.120.500.250.030.020.020.250.030.061.00.250.120.020.038.00.030.061.00.500.120.020.028.00.250.250.254.00.250.2564.0CAS64.00.50.5016.064.08.00.501.0643870.251.02440.250.25520.2516.0210.120.061.0130.250.030.12101.08.0160.062020.250.061.01.0940.500.250.500.50Cuenca-EstrellaM.Antimicrob.AgentsChemother.2006Mar,50:917.B3750.500.501.01.00.504.02.01.01.01102.0550.25748.0(iv)BBABCDBABLD)BLIPOSOMECmax/AUC/AE++++++++++++++mg/(kg.d)0.6~13~453~5123PK/PDBt1/224h48h2%5%80%11%t1/225h30hCYP4503A4,35h3%18%6h80%CYP2C19CYP3A4CYP2C95%t1/225-31h775-t1/22.5h6h,t1/290%™Plasmaconcentrations(mg/L)Plasmaconcentrations(mg/L)10024487296120144168Hoursafterdose1010.12mg/kg2mg/kg0.6mg/kg0.6mg/kgBBMICMIC0.7mg/kgamphotericinB4hcontinuousinfusion0.7mg/kgamphotericinB0.7mg/kgamphotericinB4hcontinuous4hcontinuousinfusioninfusionBekerskyetal2002AntimicrobAgentsChemother;46:828-33.()55%90%11.7L/kg4.6L/kg9.7L/kg1-2×1-2×1×Low0.5-1×Low99%58%97%NoNoNoCYP3A4CYP2C19/3A4non-oxidative34±9h6-9h9-11hRef:FDATMICAUCMICTMIC,,AUC/MICAntifungalseffectPAEPK/PDTargetTriazolesStatic/?+TimeA/M255-FCStatic/?+/-TimeTM25-50AmBFungicidal+ConC/MEchCandidaFungicidal+ConC/MaspergillusFugistatic+/-Con/time3-10‹‹‹ABCTakemotoKetal,Microbio.Immunol.,50(8),579-586,2006AntimicrobialsAgentsChemother.2006Mar;50(3):935-42.B15mg0.020.1mg/kg5mg0.60.7mg/kg1mg/kg1211.53.0g1362030mg10ml50mg5ml25mg5%()10mg/100ml6pH4.24g2550mg25mgBzzDiagnosticMicrobiologyandInfectiousDisease,38(2000)87–93PK/PDTABLE.FluconazoleED50inthetreatmentofdisseminatedC.albicansorganismswithvariousinvitrosusceptibilitiesOrganismMIC(mg/liter)ED50(mg/kg)AUC/MICR2(%)C.albicansK-10.51.92496C.albicans98-1716611294C.albicans98-234321142096ANTIMICROBIALAGENTSANDCHEMOTHERAPY,Oct.2003,p.3165–3169FIG..Relationshipbetweenthetotalandfreedrug24-hAUC/MICratioandthechangeinlog10CFUperkidneys(yaxis)after1dayoftreatmentwithvoriconazolefor10C.albicansorganisms.Eachsymbolrepresentsdatafortwovoriconazole-treatedmice.4002004006—810092001001216mg/kg(124)*4mg/kg200mg121121–––=~FIG.1.Time-killassayofVER-002andamphotericinBagainstC.albicansinantibioticmedium3.ConcentrationsofVER-002(VER)andamphotericinB(AmB)at0.01,0.1,and0.25mg/mlwerestudiedinrelationtoagrowthcontrol.Dataplottedarethemean6SEMfromthreeseparateexperimentsforeachgrowthcurve,includingthecontrolandamphotericinBat0.25mg/ml.AstheSEMwassmallforseveraltimepoints,theerrorbarsmaynotalwaysbeapparentinthetime-killcurves.Table.Pharmacokinetic/pharmacodynamicparameters,pulmonaryfungalburden,andsur-vival,inimmunosuppressedmiceinoculatedintranasallywithAspergillusfumigatus.CaspofunginCaspofungindoseandinterval96-hAUC:MECratioCmax:MECratiot1MEC,%CE,mean(~SE),log1096-hsurvival,%0.0625mg/kgq682.641.13606.31(0.22)650.25mg/kgq24…2.812136.39(0.34)500.5mg/kgq48…5.448155.49(0.14)550.25mg/kgq6330.604.560954.32(0.26)851.0mg/kgq24…11.250503.33(0.27)802.0mg/kgq48…21.950333.00a(0.36)751.0mg/kgq61322.0018.2401004.38(0.33)754.0mg/kgq24…45.000885.06(0.40)708.0mg/kgq48…87.800524.80(0.35)85zzz5-FCFIG.4.(a)RelationshipbetweenthepercentageofthedosingintervalthatlevelsinserumremainedabovetheMICfortheorganismandlog10numberofCFUperkidneysafter24hofflucytosinetherapy.Eachsymbolrepresentsdataforfourkidneys.(b)Relationshipbetweenthe24-hAUC/MICandlog10numberofCFUperkidneysafter24hoftherapy.Eachsymbolrepresentsdatafortwomice(fourkidneys).(c)Relationshipbetweenthepeaklevelinserum/MICandlog10numberofCFUperkidneysafter24hoftherapy.Eachsymbolrepresentsdatafortwomice(fourkidneys).ANTIMICROBIALAGENTSANDCHEMOTHERAPY,Apr.2000,p.938–942FIG.3.Relationshipbetweenthe24-htotaldoseofFlucytosineforfourlengtheningdosingintervalsandlog10numberofCFUperkidneysinaneutropenicmurinemodelofdisseminatedca