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