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