Pharmacodynamic (PD) evaluation of Rezafungin...disseminated candidiasis model using an extended...
Transcript of Pharmacodynamic (PD) evaluation of Rezafungin...disseminated candidiasis model using an extended...
Pharmacodynamic (PD) evaluation of Rezafungin (CD101) against Candida auris in the persistently
neutropenic murine model of disseminated candidiasis
AlexanderJ.Lepak,MiaoZhao,DavidR.AndesUniversityofWisconsinSchoolofMedicineandPublicHealth
TransparencyDeclaration
• ThisstudywassupportedbyfundingfromCidara Therapeutics,Inc.
Candidaauris - Background• Globalemergingpathogen
• Mortalityrate40-60%
• Environmentalpersistenceandinterhuman transmission
• Drug-resistanceandmulti-drugresistanceistypical
• Fluconazoleresistance>90%
• AmphotericinBresistance30-50%
• Echinocandinresistance5-10%Lamoth F&Kontoyiannis DP.JInfec Dis2018
Rezafungin(CD101)
• Novelechinocandinwithtoxicologicalandpharmacokineticadvantagesincludingaprolongedterminalhalf-lifeof130-hoursinhumans
• Developedforextendedintervaldosing(i.e.once-weeklyintravenousinfusions)
• EchinocandinPK/PDstudieshave
demonstratedtheimportanceofboth
AUC/MICandCmax/MIC
• Rezafunginpharmacologicalproperties
allowformaximizingbothPDindices
Rezafungin Acetate
LepakAJetal,AAC2018LakotaEAatal,AAC2018
PreviousRezafungin MurinePK/PDTargetStudies
C.albicans C.glabrata C.parapsilosisStasis 1-logkill Stasis 1-logkill Stasis 1-logkill
24hfAUC/MIC* 2.89 5.14 0.20 0.66 ~3 NA
LepakAJ,etal.Antimicrob AgentsChemother 2018;62:e02154-17
*PDtargetsarenumericallylower(especiallynotableforC.glabrata)thancomparatorechinocandins
CurrentStudyAim: DeterminethepharmacodynamictargetfortreatmentofdisseminatedC.aurisinfectionintheneutropenicmurinemodelofinvasivecandidiasis
MethodsStrains:• 4C.aurisstrains(oneFKSmutantstrain)
Susceptibilitytesting:• MICsbyCLSImethods
MurinePK:• PlasmaPKfromgroupsofmiceafterIPadministrationofrezafunginat1,4,16,and64mg/kg
• Non-compartmentalmodel
InfectionModelandAnalysis:• 6-weekoldSwiss/ICRfemalemice(23-27g)• Neutropeniabycyclophosphamideinjectionatday-4,-1,+2and+4
• Inoculumof5.99±0.29log10CFU/mLinjectedintotailvein,2-hourslaterfirstdoseofdrugisadministered
• Rezafungindose(1,4,16or64mg/kg)IPonday0,3,6tomimiconce-weeklydosinginhumans
• Infectiousburdenenumeratedfromkidneysonday7byCFUcounts
• TreatmentdataandAUC/MICevaluatedbysigmoidEmaxmodel(Hillequation)
• Staticand1-logkilltargetexposuresweredetermined
StrainsandinvitroSusceptibilityTesting
Strain CountryofOrigin
Log10 growthinUntreatedControls(CFU/kidneys)
In vitroSusceptibilityResults(mg/L)Rezafungin Fluconazole Micafungin AmphotericinB
B11220 Japan 3.06 0.06 4 0.125 0.38B11785 Colombia 3.43 0.125 8 0.5 1.5B11799 Colombia 3.67 0.25 16 2 0.5B11211* India 3.17 2 256 4 1.5
*FKS1_HS1_S639F
MurinePharmacokinetics
Plasmaconcentrationsofrezafungin (CD101)inmicefollowingsingleIPdoses.Eachsymbolisthemeanandstandarddeviationforthreemice.Cmax,peakconcentration,AUC,areaunderconcentration-timecurvefromzerotoinfinity,T1/2,terminaleliminationhalf-life
TreatmentStudies
Rezafungin dose-responsecurvesagainstC.auris(left).Relationshipbetweentotal- (red)andfree- (blue)drugAUC/MICandtherapeuticeffect(right).Groupsofmiceweretreatedwithoneoffourrezafungin dosingregimensadministeredeverythreedaysoverthe7dayexperimentalperiod.Infectiousburdenwasenumeratedfromkidneyhomogenatesandcomparedtotheburdenattimepointzero(dashedline).Pointsabovethedashedhorizontallinerepresentnetincreaseinburdenovertimeandthosebelowthelinerepresentanetdecrease.PDparametersarealsoshowninthefigureontherightincludingregressionanalysis.
PDTargetExposuresAssociatewithNetStasisand1-logkillEndpoints
Strain MIC (mg/L)
Static Dose (mg/kg)
Stasis Ave 24 h AUC/MIC
Stasis Ave 24 h fAUC/MIC
1 log kill dose (mg/kg)
1 log kill Ave 24 h AUC/MIC
1 log kill Ave 24h fAUC/MIC
B11220 0.06 0.87 144.78 1.16 6.99 987.68 7.90B11785 0.125 6.09 421.39 3.4 10.65 685.80 5.49B11799 0.25 8.76 288.72 2.3 16.17 488.81 3.91B11211 2 23.04 82.95 0.66 NA*Mean 9.69 234.46 1.88 11.27 720.76 5.77Median 7.43 216.75 1.73 10.65 685.80 5.49Std Dev 9.48 151.53 1.21 4.62 251.26 2.01
*NA,notachieved
HumanExposure
• TranslatingPK/PDtargetstohumans
• Rezafungin 400mgIVonceweeklyinhumans
• TotalAUC0-168 1840mg*h/L,2.6%freedrug--->47.84mg*h/LfreeAUCoraverage24h
freedrugAUCofabout7mg*h/L
• UsinghumanfreedrugPKestimatesandstasisPDtargetsyieldsanMICceilingestimate
of2-4mg/L,for1-logkilltargettheMICceilingestimatewouldbe1-2mg/L
Conclusions
• Rezafungin demonstratedinvivopotencyagainstC.auris intheneutropenic
disseminatedcandidiasismodelusinganextendedintervaldosingregimentomirror
humandosingregimens
• Efficacywasdemonstratedagainstahighlyresistantstrain(B11211)withknownFKS1mutation
• PK/PDtargetexposuresoffreedrug24hAUC/MICof2and6ledtostasisand1-log
kill,respectively
• Rezafungin isavaluableadditiontotheantifungalarmamentarium,withPK
advantagesthatpermitachievementofoptimalPK/PDdrugexposuresinextended-
intervaldosingregimensandagainststrainswithelevatedechinocandinMICs