excluded200gana-894

AFirst-in-HumanRandomized,Double-Blind,Placebo-Controlled,Single-andMultiple-AscendingOralDoseStudyofNovelAntimalarialSpiroindoloneKAE609(Cipargamin)ToAssessItsSafety,Tolerability,andPharmacokineticsinHealthyAdultVolunteersF.
JoelLeong,aRuobingLi,bJayPrakashJain,cGilbertLefèvre,dBaldurMagnusson,dThierryT.
Diagana,aPeterPerteleNovartisInstituteforTropicalDiseases,Singaporea;NovartisInstitutesforBioMedicalResearch,Beijing,People'sRepublicofChinab;NovartisHealthcarePrivateLimited,Hyderabad,Indiac;NovartisPharmaAG,Basel,Switzerlandd;NovartisInstitutesforBioMedicalResearch,Cambridge,Massachusetts,USAeThisrst-in-humanrandomized,double-blind,placebo-controlled,ascending-singleand-multipleoraldosestudywasdesignedtoevaluatethesafety,tolerability,andpharmacokineticsinhealthyvolunteersofKAE609(cipargamin;formerlyNITD609),aspiroindolonenowintrialsformalariatreatment.
Itwasstudiedinsingle-dosecohorts(1to300mg,includingone30-mgfoodeffectcohort)with4to10subjectsineachcohortandinmultiple-dosecohorts(10to150mgoncedailyfor3days)with8sub-jectsineachcohort.
Thefollow-upperiodwas6to8dayspost-lastdose.
Safetyandpharmacokineticswereassessedatscheduledtimepointsduringthestudy.
Systemicexposureintermsoftheareaundertheconcentration-timecurvefrom0hextrapolatedtoinnity(AUC0–)increasedinadose-proportionalmanneroverthedoserangeof1to300mg.
TheAUCfromtimezerotothetimeofthelastquantiableconcentration(AUClast)andthemaximumconcentrationofdruginplasma(Cmax)alsoincreasedinanapproximatelydose-proportionalmanner.
Whenadministereddailyfor3days,theaccumulationratioonday3(theAUCfromtimezeroto24hpostdosing[AUC0–24]onday3/AUC0–24onday1)wasintherangeof1.
5to2inthestudieddoserange(10to150mg)andwasconsistentwithaneliminationhalf-lifeofaround24h.
UrineanalysisforunchangedKAE609revealednegli-gibleamounts(<0.
01%)wereexcretedrenally.
ThehighfatfoodintakedidnotaffecttheextentofKAE609absorption(AUC);however,theCmaxwasreducedbyaround27%.
KAE609wastoleratedinthisstudy,withtransientgastrointestinalandgenito-urinaryadverseeventsofmildtomoderateintensity(semendiscoloration,diarrhea,nauseaandabdominaldiscomfort,dizzi-nessandheadache,cathetersitehematoma).
Gastrointestinalandgenitourinaryadverseeventsincreasedwithrisingdoses.
Artemisininderivativesincombination(e.
g.
,Coartem)arecurrentlythetreatmentofchoiceforfalciparummalariain-fections.
However,artemisininresistancehasnowbeendocu-mentedinSoutheastAsia(1–3),andthereisanurgentneedfornewantimalarialstoaddressthisthreat(4–8).
Twonewclassesofantimalarialshavebeendiscovered:thespiroindolones(9,10),followedbytheimidazolopiperazines(11,12).
KAE609(cipar-gamin;previouslyknownasNITD609)isaspirotetrahydro--carbolines(spiroindolone)andtherstnewantimalarialchemo-typein2decades.
Thespiroindoloneclasswasidentiedbyusinghigh-throughputphenotypicscreening(13,14)andisbelievedtoinhibitPfATP4,aparasiteplasmamembraneNa-ATPase,whichresultsindisruptionofparasitesodiumhomeostasis(15).
KAE609hasalownanomolar50%inhibitoryconcentrationagainstdrug-sensitivePlasmodiumstrainsandisequallypotentagainstvariousdrug-resistantstrains.
Invitrostudiesindicateac-tivityonbothasexualandsexualformsoftheparasite,includingagainststage5Plasmodiumfalciparumgametocytes(10).
Inanexperimentalmalariamousemodel,KAE609wasmoreactivethanartemether,andsingle-dosecurehasbeendemonstratedinaPlasmodiumbergheirodentmodelofblood-stagemalaria(9).
Thispotentantimalarialactivityobservedinapreclinicalrodentmodelwasborneoutinahumanmalariapatienttrial,whichfollowedthisrst-in-humanstudybutwaspublishedinadvance(16),thatshowedthatKAE609clearsparasitemiarapidlyinfalciparumandvivaxmalariapatients.
Theobjectivesofthisrst-in-humanstudyweretoassessthesafetyandtolerabilityofKAE609inhealthyadultvolunteersaftersingleandmultipleoraldosingandtoassessthepharmacokineticsaftersingle(includingfoodeffect)andmultipledosing.
MATERIALSANDMETHODSStudydesign.
Thiswasasingle-center,double-blind,randomizedplace-bo-controlledtrial.
Itwasconductedfrom16November2010to4Octo-ber2011attheQ-PharmPhaseIUnit(Brisbane,Australia).
Thisstudycomprisedtwoparts.
Part1involvedsingle-ascendingdose(SAD)cohortswithdifferentdoselevelsofKAE609(1mg,3mg,10mg,30mg,100mg,200mg,300mg)andonefoodeffectcohort(30mg)with4to10subjects(includingplacebo)ineachcohort.
Itconsistedofamaximum28-dayscreeningperiod,abaselineperiod(day1),treatmentperiod(days1to5),andasinglestudycompletionevaluationconductedbetween6to8daysafterthedose.
Thefollow-upperiodwas6to8dayspostdose.
Part2examinedmultiple-ascendingdose(MAD)cohortsadminis-tereddifferentdoselevels(10mg,30mg,60mg,100mg,and150mgonceReceived20May2014Returnedformodication11June2014Accepted1August2014Publishedaheadofprint11August2014AddresscorrespondencetoJoelLeong,joel.
leong@novartis.
com.
Copyright2014Leongetal.
Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttribution3.
0Unportedlicense.
doi:10.
1128/AAC.
03393-14October2014Volume58Number10AntimicrobialAgentsandChemotherapyp.
6209–6214aac.
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Itcomprisedamaximum28-dayscreeningperiod,abaselineperiod(day1),treatmentperiod(days1to7),andasinglestudycompletionevaluationconductedonday9,day10,andday11(whichwas6to8daysafterthelastdose).
Thefollow-upperiodwas6to8daysafterthelastdose.
Studytreatmentwasadministeredorallywith180to350mlofwater,withmouthcheckstoensurecompliance.
Allsubjectsfasted(i.
e.
,nofoodandliquidexceptwater)foratleast10hpriortoadministrationofstudydrugandcontinuedfastingforatleast4hthereafter.
Nouidintakeapartfromtheuidgivenatthetimeofdrugintakewasallowedfrom2hbeforeuntil2hafterdosing.
Subjectsdidnotconsumeanycarbonateddrinks,andconsumptionofalcohol,caffeine,tobacco(ornicotine-containingproducts),orgrapefruit(orrelatedcitrusfruit)wasnotpermittedduringthestudy.
SubjectswhowereenrolledinthefoodeffectcohortweregiventhestandardFDAbreakfast(17)anddosedwithKAE609within5minaftercompletionofthemeal.
Prescriptionandnonprescriptiondrugsanddietarysupplementswerenotpermittedandhadtobediscontinuedwithin30daysor5half-lives(whicheverwaslonger)priortotheenrollment.
Treatmentwastobediscontinuedintheeventofthedevelopmentofcommonterminologycriteriaforadverseevents(CTCAE;version4.
0)grade2severity(orgreater)gastrointestinal,pulmonary,orblood/bonemarrowabnormali-tiesorifexposure(i.
e.
,theareaundertheconcentration-timecurvefromtimezeroto24hpostdose[AUC0–24])ofKAE609exceeded38,800ng·h/ml,themeanexposureobservedindogsforthehighestdoseconsideredsafe(5mg/dayfor14days)inGoodLaboratoryPractice(GLP)studies.
Subjectscouldbediscontinuedfromthestudyattheirownrequestforsafety,behavioral,oradministrativereasonsorforanyotherreasonatthediscretionoftheinvestigatororsponsor.
ThisstudywasconductedincompliancewiththeDeclarationofHel-sinkiandGoodClinicalPracticeGuidelinesestablishedbytheInterna-tionalConferenceonHarmonization.
Thenalprotocol,amendments,andinformedconsentdocumentationwerereviewedandapprovedbythestudycenter'sInstitutionalReviewBoard.
Allsubjectsprovidedwritten,informedconsentbeforeparticipatinginanystudyprocedures.
Subjects.
Thestudyplannedtoenroll94subjects(46subjectsinpart1and48subjectsinpart2),includingbothhealthymaleandfemalesubjects(ofnon-child-bearingpotential),aged18to55years,ofanyethnicorigin,ofatleast50kginweight(withbodymassindexbetween18and30kg/m2)whopassedscreeningassessments,metinclusion/exclusioncriteria,andprovidedwrittenconsent.
Healthstatuswasdeterminedbymedicalhistory,physicalexamina-tion,andlaboratorytestsatscreening.
Onlyfemaleswithnochild-bearingpotentialwereallowedtoenroll,andallfemalesubjectswererequiredtohaveanegativepregnancytestresultatscreeningandatthebaseline.
Maleswererequiredtocomplywithbarriercontraceptionmethodsdur-ingthestudyandupto3weeksafterthelastdose.
Exclusioncriteriaincludeduseofinvestigationaldrugswithin30daysor5half-livesofenrollment(whicheverwasgreater);historyofclinicallysignicantelec-trocardiogramabnormalities;historyoforgansystemmalignancywithinthelast5years(excludingskinbasalcellcarcinoma);pregnancyorchild-bearingpotential;useoftobaccoproductswithintheprevious3months;useofprescriptionmedicationsorherbalsupplementswithintheprevi-ous4weeksorover-the-countermedication(exceptforincidentalacet-aminophen),dietarysupplements,orvitaminswithin2weeks;blooddo-nationorbloodlossof400mlwithintheprevious8weeks;and/orahemoglobinlevelof12.
0g/dl.
Subjectswerealsoexcludediffoundtohavehadsignicantillnesswithintheprevious2weeks;historyoffoodallergiesoranysurgicalormedicalconditionwhichmightsignicantlyalterdrugpharmacokinetics;historyofimmunodeciencydisease;posi-tivehepatitisBorCtestresult;and/orahistoryofdrugoralcoholabuseintheprevious12monthsorevidencethereof.
Safetyassessment.
Safetyevaluationsincludedadverseeventcounts,monitoringforseriousadverseeventswiththeseverityandrelationshiptothestudydrug,monitoringforpregnancies,andregularmonitoringofhematology,bloodchemistry,urinalysis,vitalsigns,physicalcondition,bodyweight,andelectrocardiogram.
Pharmacokineticparametersandassessment.
Inpart1ofthestudy(singledosing),bloodsampleswerecollectedpredosingand0.
5,1,2,3,4,6,8,12,24,36,48,72,and96hpostdose.
Urinesamples(10-mlaliquots)werecollectedfromthefastingcohortsthatreceivedasingledoseof30mg,onlyatpredose,andattheendofeachofthefollowingperiods:0to12hpostdose,12to24hpostdose,and24to48hpostdose.
Inpart2(dailydosingfor3days),bloodsamplingonday1occurredatpredoseand0.
5,1,2,3,4,6,8,12,and24hpostdose.
Onday3,bloodsampleswerecollectedatpredoseand0.
5,1,2,3,4,6,8,12,24,36,48,72,96,120,and144hpostdose.
Forbioanalysis,plasmasamplepreparationconsistedofproteinpre-cipitation,evaporationoftheltrate,andanalysisofthereconstitutedsample.
A10-laliquotofthereconstitutedextractwasanalyzedbyliquidchromatography-tandemmassspectrometry(LC-MS/MS)inmultiplereactionmonitoring(MRM)modeusingelectrosprayionization(ESI)astheionizationtechnique.
KAE609[M6]wasusedastheinternalstan-dard.
Thelowerandupperlimitsofquanticationwere1.
00ng/mland5,000ng/ml,respectively,whenweused0.
0500mlofplasma.
KAE609isstableinhumanplasmaforatleast24hatroomtemperature,after3freeze-thawcycles,andforatleast322daysafterstorageatorbelow60°C.
Thecoefcientofvariation(CV;precision)andpercentbias(ac-curacy)forthemultiplerunsduringtheperiodofanalysisforvequalitycontrolsamplesof2.
00,5.
00,400,2,000,and4,000ng/mlwere9.
8and2.
0,4.
9and2.
4,6.
1and5.
3,and6.
8and2.
0,respectively.
TheurinebioanalysismethodconsistedofsampledilutionwithaninternalstandardandanalysisofthealiquotbyLC-MS/MSintheMRMmodebyusingESIastheionizationtechnique.
Thelowerandupperlimitsofquanticationwere1.
00ng/mland5,000ng/mlusing0.
0500mlofurine.
TheCVandbiasforthemultiplerunsduringtheperiodofanalysisforsixqualitycontrolsamplesof1.
00,2.
00,5.
00,400,2,000,and4,000ng/mlwere14.
1and12.
0,4.
3and10.
0,6.
0and17.
6,5.
1and5.
5,5.
4and17.
5,and6.
8and2.
0,respectively.
Pharmacokineticparameterswerederivedbyusinganoncompart-mentalmethodwithinWinNonlinPro(version5.
2).
Thefollowingpharmacokineticparameterswerederivedforpart1:theAUC0–24;AUCfromtimezerotothetimeofthelastquantiableconcentration[AUClast;(masstime)/(volume)];AUCfromtimezeroextrapolatedtoinnity(AUC0–);maximumobservedconcentration(Cmax);eliminationhalf-life(t);apparentoralclearance(CL/F);apparentvolumeofdistributionduringtheterminaleliminationphasefollowingextravascularadminis-tration(Vz/F).
Forpart2,thefollowingpharmocokineticvaluesweredetermined:AUC0–24,Cmax,Tmax(forday1andday3),t(post-day3dosing),andtheaccumulationratio[Racc;(AUC0–24onday3/AUC0–24onday1)].
Inaddition,theamountofdrugexcretedintotheurinefromtimezerototimet(Ae0–t)andrenalclearanceweredeterminedforpart1fromtheurinedrugconcentration-timedatacollectedfromsubjectswhoreceived30-mg,100-mg,or200-mgdoses.
Statisticalmethods.
Pharmacokineticparametersweresummarizedusingarithmeticmeansandstandarddeviations,exceptforTmax,forwhichmedianvaluesandrangesarereported.
Totestdoseproportional-ity,theprimarypharmacokineticparameterswereanalyzedbyusingaregressionmodelonthelog-transformedpharmacokineticparameters(AUClastand/orAUC0–andCmax)versuslog-transformeddose,anddoseproportionalitywasassessedwithalack-of-ttest.
Theanalysesweredoneseparatelyforthesingle-andmultiple-dosecohortsandseparatelyondays1and3forthemultiple-dosecohorts.
Inthefoodeffectcohort,thegeometricmeanratioofprimarypharmacokineticparametersunderfedandfastedconditionsarereportedalongwith90%condenceinter-vals(CI),whichweredeterminedfromamixedlinearmodelwithxedeffectsforfasted/fedconditionandarandomsubjecteffect.
Adverseeventsweresummarizedbytreatmentgroup,preferredterm,andseverity,withformalstatisticalanalysisperformedifadose-relatedtrendwasapparent.
Leongetal.
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Atotalof95subjectswereenrolledandanalyzed(46subjectsinpart1and49subjectsinpart2),and93subjectscompletedthestudy.
Instudypart1(singledosing),onesubjectwhocompletedthetreatmentandassessmentsinthe30-mgsingle-dosefastedcohortwasfoundtohaveanelevatedtotalbilirubinlevel(26mol/liter)whenhereturnedforhissec-ondbaselineentrycriteriacheckforthefoodeffectcohort(30-mgsingledose,fed)andwasconsequentlyexcludedandwithdrawn,resultinginonly34of35subjectsinthepooledgroupcompletingthestudy.
Instudypart2,therewasonesubjectwhodidnotcompletethestudyduetowithdrawalofinformedconsentonday1afteradministrationoftherstdoseandassessment,resultinginonly45of46subjectsinthepooledgroupcompletingthestudy.
Thissubjectdidnothaveanyclinicallysignicantabnormalitiesrecorded.
Allsubjectsweremale,andthemajoritywerewhite(94.
68%).
ThedemographicsandotherbaselinecharacteristicsareshowninTable1.
Safetyandtolerability.
All95randomizedsubjectswerein-cludedinthesafetyanalysis.
Therewerenodeathsorseriousad-verseevents.
TheoverallincidenceofadverseeventswashigherinsubjectsadministeredKAE609thanthosegivenplacebo,withtheincidenceincreasingwithdose.
Moresubjectsexperiencedad-verseeventsinthemultiple-dosingcohortsthansingle-dosingcohorts(73%versus50%),andproportionallymoreofthesewereconsidereddrugrelated(62.
2%versus19%).
GastrointestinaleventsweremorefrequentinsubjectswhoreceivedKAE609.
Alleventsweremildormoderateinseverity,withmostassessedasmildandresolvingspontaneously.
Aftersingledoses,50.
0%(21/42)and15.
4%(2/13)ofsubjectsadministeredKAE609andplacebo,respectively,developedoneormoreadverseevents.
Fiveeventsoccurredin2ormoresubjectsadministeredanydoseofKAE609orplacebo.
FoureventsonlydevelopedinsubjectsreceivingKAE609:semendiscoloration(16.
7%),diarrhea(7.
1%),nausea(7.
1%),andfatigue(4.
8%).
HeadachewasreportedinsubjectsadministeredKAE609(11.
9%)orplacebo(7.
7%).
Aftermultipledoses,73.
0%(27/37)and50.
0%(6/12)ofsubjectsadministeredKAE609andplacebo,respectively,developedoneormoreadverseevents.
Seveneventsoccurredin2ormoresubjectsadministeredanydoseofKAE609orplacebo.
FoureventsonlydevelopedinsubjectswhoreceivedKAE609:dizziness(10.
8%),cathetersitehematoma(8.
1%),backpain(5.
4%),andnausea(5.
4%).
ThreeeventswerereportedinsubjectsadministeredKAE609orplacebo,includingheadache(45.
9%ver-sus33.
3%,respectively),semendiscoloration(59.
5%versus8.
3%),andcontusion(2.
7%versus16.
7%).
Theeventsmoreoftenassessedasrelatedtothestudydrugweresemendiscolorationandheadache,withthisassessmentmadeamongsubjectsadminis-teredKAE609andthoseadministeredplacebo.
Therewerenoclinicallysignicantabnormalbloodpressuremeasurements,andnohypotensionorvomitingwasassociatedwiththereporteddiz-ziness.
OnesubjectwhoreceivedmultipledosesofKAE609developedelevatedbloodalaninetransaminase(ALT),aspartatetransami-nase(AST),lactatedehydrogenase(LDH),andcreatinekinase(CK)levelsthatwereassessedasmildadverseevents,butthesewerenotattributedtothestudydrug.
Hisbilirubinlevelwaswithinthenormalrangeandliverenzymeabnormalitiesresolvedwithin4days.
Onesubjectwhoreceivedmultipledosesofplacebodevelopedelevatedbloodamylaseandlipaselevelsthatwereas-sessedasmildadverseevents;bothweresuspectedtoberelatedtothestudydrug.
VitalsignmeasurementsandECGmeasurementsdidnotre-vealanyabnormalitiesdeterminedtobeclinicallysignicantbytheinvestigatorinanysubject.
Meanandmedianvaluesformea-suredhematologyandbloodchemistryparameters(includingALT,AST,LDH,andbilirubin)remainedwithinthenormalrangefrombaselinetotheendofthestudy,withtheexceptionoftwoelevatedndings(ASTandALT)attheend-of-studyvisitinthe100-mgonce-daily(q.
d.
)3-daycohort;thesendingsweresolelyattributabletothesubjectpreviouslydescribed.
Therewerespo-radicindividualhematology,chemistry,orurinalysisparametersthatwereoutsidethenormalrangeduringthestudy.
Thesewereclassiedbytheinvestigatorasnotclinicallysignicantornotdrugrelated.
Therewere7subjectsinstudypart1and22subjectsinstudypart2whoreportedyellowsemendiscolorationafterbeingdosed.
Thisoccurredatdifferentdoselevels:1subjectonthesingle200-mgdose,6subjectsonthe300-mgsingledose,5subjectsonthe60-mgdailydosefor3days,11subjectsonthe100-mgdailydosefor3days,and6subjectsonthe150-mgdailydosefor3days.
Intotal,thisaffected29/79(36.
7%)subjectswhoweretakingtheactivedrug.
Yellowdiscolorationofsemenwasconrmedinlab-oratoryexaminationofcollectedsemensamples,whichwerevol-untarilyprovidedbymostsubjectsafterthisadverseeventwasreported.
Therewasnoazospermia,diminishedmotility,orclin-icallysignicantabnormalitiesreported.
Uponfurtherinvestigationconductedafterthisevent,noKAE609wasdetectedinejaculate.
However,threeprimarymetab-olitesofKAE609(M18,M23,andM48)werepresent,twoofTABLE1DemographicsandotherbaselinecharacteristicsParameterPart1Part2KAE609(n35)Placebo(n11)Total(n46)KAE609(n37)Placebo(n12)Total(n49)Meanage,yrs(range)25.
2(18–45)24.
6(18–32)25.
1(18–45)25.
4(18–47)23.
1(20–29)24.
8(18–47)No.
(%)of:Caucasians33(94.
3)11(100)44(95.
7)33(89.
2)12(100)45(91.
8)Asians1(2.
9)0(0.
0)1(2.
2)4(10.
8)0(0.
0)4(8.
2)Others1(2.
9)0(0.
0)1(2.
2)0(0.
0)0(0.
0)0(0.
0)Meanwt,kg(range)76.
2(51–98)79.
2(58–105)76.
7(51–105)76.
7(54–93)77.
0(70–91)76.
7(54–93)Meanht,cm(range)179.
6(166–194)178.
0(164–187)179.
2(164–194)179.
7(163–193)180.
3(171–192)179.
9(163–193)AntimalarialSpiroindoloneKAE609/CipargaminFIHStudyOctober2014Volume58Number10aac.
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Ofthetwometabolitesdetected,theM23colorwasdemonstratedinthelaboratoryatorbelowconcentrationsdetectedinsemen.
WeinferredthatthecolorseenwasduetometaboliteM23.
Themainmetabolite(M23)isnotactiveagainstPlasmodiumfalciparumandshowsnocytotoxicpotentialagainstahumanhepaticcellline(unpublisheddata).
OtherminormetaboliteshavenotbeentestedagainstP.
falciparumbutarenotbelievedtobetoxicatthelevelsdetectedbasedonassessmentofsemensamples.
Pharmacokinetics.
(i)Single-doseadministrationinhealthyvolunteers(1to300mg,oraladministration).
Themeanplasmadrugconcentration-timeproleofKAE609followingoraladmin-istrationofa1-to300-mgdoseispresentedinFig.
1.
Thephar-macokineticparametersaresummarizedinTable2.
Cmaxwasintherangeof14ng/ml(forthe1-mgdose)to2,090ng/ml(forthe300-mgdose),withamedianTmaxintherangeof1to5h.
AtrendforanincreasingTmaxwithincreasingdosehasbeenobserved,andatthehighestdoseof300mg,theTmaxwasintherangeof3to8.
15h.
TheAUClastwasintherangeof0.
17h·g/mlto79.
7h·g/mloverthe1-to300-mgdoserange.
SystemicexposureintermsoftheAUC0–(slope,1.
04;90%CI,0.
99to1.
09)increasedinadose-proportionalmanneroverthedoserangeof1to300mgofKAE609.
TheAUClast(slope,1.
07;90%CI,1.
03to1.
12)andCmax(slope,0.
89;90%CI,0.
85to0.
92)alsoincreasedinanapproxi-matelydose-proportionalmanner.
TheCmaxexhibitedbetterpro-portionalityinthedoserangeof1to200mg;however,at300mgitwasslightlylessthanproportional,mostprobablyduetothelowaqueoussolubilityofKAE609(pBCSclassII).
KAE609waselim-inatedwithaterminaleliminationhalf-life(T)intherangeof19to26hoverthe1-to300-mgdoserangeinhealthysubjects.
Theapparentvolumeofdistributionandapparentclearancerangedbetween126to194litersand4to5.
5liters/h,respectively,overtheentiredoserange.
(ii)Multiple-doseadministrationinhealthyvolunteers(10to150mgq.
d.
for3days,oraladministration).
Theday1andday3superimposedmeanplasmadrugconcentration-timeprolesofindividualdoselevels(10,30,60,100,and150mgdailyfor3days)followingoraladministrationofKAE609arepresentedinFig.
2.
ThepharmacokineticparametersaresummarizedinTable3.
ThemeanCmaxandAUC0–24onday1wereintherangeof120to1,170ng/mland1.
24to15.
1g·h/ml,respectively.
Thecorrespondingvaluesforday3were161to1,770ng/mland1.
91to29.
4g·h/ml,respectively.
Overthecompletedoserange,themedianTmaxrangedfromaround1.
5to3h.
SystemicexposureintermsoftheAUClastonday3(slope,1.
00;90%CI,0.
94to1.
07)increasedinaFIG1Arithmeticmeanlinearplasmadrugconcentration-timeprolesforKAE609followingoraladministrationofsingleascendingdoses(SAD,part1).
Errorbarsrepresent1SD.
TABLE2SummaryofpharmacokineticparametersofKAE609followingoraladministrationofsingleascendingdoses(part1)PharmacokineticparameterMeanSDfordosegroup1mg(n3)3mg(n3)10mg(n3)30mg(n8)100mg(n6)200mg(n6)300mg(n5)AUC0–24(g·h/ml)0.
1270.
0440.
3880.
1261.
020.
0924.
290.
72511.
51.
5123.
74.
9936.
02.
40AUClast(g·h/ml)0.
1690.
0540.
6090.
251.
750.
287.
481.
9823.
14.
0151.
816.
079.
715.
8AUC0–(g·h/ml)0.
217a0.
660.
251.
860.
32182.
4723.
54.
2353.
717.
881.
317.
7Cmax(ng/ml)14.
13.
5035.
47.
971056.
9536457.
683014116403052090482Tmax(h)b1(1.
0–1.
0)2(2.
0–2.
0)2(2.
0–2.
02)2.
52(1.
0–3.
02)3(2.
0–4.
0)3.
51(2.
0–6.
0)5.
43(3.
0–8.
15)T1/2(h)19.
44.
3223.
52.
6524.
82.
4623.
25.
0522.
24.
9725.
69.
0724.
07.
59CL/F(liters/h)5.
181.
174.
921.
515.
490.
994.
031.
074.
400.
934.
081.
333.
851.
0Vz/F(liters)14961.
116962.
319416.
912924.
013824.
814139.
012417.
7aDeterminedforonlytwosubjects.
bTmaxvaluesaremedians(withrangesshowninparentheses).
FIG2Arithmeticmeanday1andday3superimposedplasmadrugconcen-tration-timeprolesfollowingoraladministrationofKAE609inmultipleas-cendingdoses(10,30,60,100,and150mg;MAD,part2).
Errorbarsrepresent1SD.
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Theday3Cmax(slope,0.
86;90%CI,0.
80to0.
93)alsoincreasedinanapproximatelydose-proportionalmannerbutwasnotconsideredstatisticallydoseproportional.
Theeliminationhalf-lifewasnotcalculatedonday1becauseoftheq.
d.
dosingofKAE609.
Theeliminationhalf-lifewasintherangeof21to28hoverthe1-to150-mgdoserange.
Theaccu-mulationindex[Racc;(AUC0–24onday3/AUC0–24onday1)]wasfoundtobeintherangeof1.
54to2.
01,asexpectedduetothelong(24-h)eliminationhalf-lifeandq.
d.
dosing.
Foodeffect.
Thefoodeffect(determinedusingahigh-fatstan-dardFDAbreakfast)onthepharmacokineticsofKAE609wasevaluatedwitha30-mgsingledose.
Inacomparisonofprimarypharmacokineticparametersunderfastandfedconditions(30mgsingledose),theextentofabsorptionwasnotaffectedsignicantlybyfoodintake.
Thegeometricmeanfed/fastratiofortheAUClastandAUC0–were1.
063(90%CI,0.
979to1.
153)and1.
016(90%CI,0.
947to1.
091),respectively.
Conversely,themeanCmaxunderfedconditions(254ng/ml)wasreducedby27%(geometricmeanfed/fastratio,0.
706)comparedtofastingcondition(356ng/ml).
TheTmaxwasdelayedfromamedianof2.
52hto4hunderfedconditions.
Therewasnomajorimpactoffoodonclearance(CL/F;4.
00liters/hforfedversus4.
03liters/hforfasted)andvol-umeofdistribution(Vz/F;129.
36litersforfedversus123.
46litersforfasted).
Exploratoryurinaryexcretion.
KAE609isminimallyexcretedviaurineinunchangedformand,onaverage,lessthanorequalto0.
01%oftheadministereddoseofKAE609wasexcretedun-changedinurineoveraperiodof48hpostdose.
Therenalclear-ance(CLr)wasintherangeof0.
438ml/hto0.
475ml/h,whichwaslowcomparedwithoverallclearance,whichwasintherangeof4to5.
5liters/h.
Consequently,urinesamplesfromothercohortswerenotanalyzedforunchangeddrug.
DISCUSSIONKAE609waswelltoleratedinthisgroupofhealthyadults,withessentiallytransientgastrointestinalandgenitourinaryadverseeventsofmildtomoderateintensity(semendiscoloration,diar-rhea,nauseaandabdominaldiscomfort,dizzinessandheadache,cathetersitehematoma).
Gastrointestinalandgenitourinaryad-verseeventsincreasedwithrisingdoses.
Theyellowdiscolorationofsemenwasanunexpectedndingandappearstobeanisolatedobservationattributabletooneormorecoloredmetabolites.
Thepresenceofdrugordrugmetabo-litesinsemenisnotunusual;caffeine(18),aspirin(19,20),andchloroquine(21,22)aresomeexamplesofcompoundsforwhichthisisreported.
Wheresampleswereprovided,wefoundnoazo-spermia,diminishedmotility,orclinicallysignicantabnormalityinsemen.
Ourresultsdemonstratedpharmacokineticapproximate-doseproportionalitywithminimalfoodeffect.
SystemicexposureintermsoftheAUCinf(slope,1.
04;90%CI,0.
99to1.
09)increasedinadose-proportionalmanneroverthedoserangeof1to300mgofKAE609.
TheAUClast(slope,1.
07;90%CI,1.
03to1.
12)andCmax(slope,0.
89;90%CI,0.
85to0.
92)alsoincreasedinanapproxi-matelydose-proportionalmanner;however,becausethecon-denceintervalsfortheslopeestimatesdidnotinclude1,thesewerenotconsideredstatisticallydoseproportional.
Theaccumu-lationratioonday3(AUC0–24onday3/AUC0–24onday1)inMADwasintherangeof1.
5to2forthestudieddoserange(10to150mg).
Theaccumulationratiowasconsistentwithanelimina-tionhalf-lifeofaround24h.
Noabsolutebioavailabilitystudiesinhumanshavebeenconductedsofar.
Atasingledoseof30mg,theextentofabsorption(AUC)wasnotaffectedbyfoodintake.
However,areducedCmax(27%)andincreasedTmax(from2.
5to4h)wereobserved.
Thiswasnotfelttobeclinicallyrelevant,becausetheefcacylikelydependsonmain-tainingadequateKAE609concentrationsthroughoutthedosingperiodandnotachievingspecicCmaxlevels.
UrineanalysisforunchangedKAE609revealedthatanegligibleamount(0.
01%)wasexcretedrenally.
Similartomanyantimalarials,KAE609ispredominantlymetabolizedintheliverbycytochromeP4503A4,theclinicalrelevanceofwhich,intermsofdrug-druginteractions,ispresentlyunknown.
Therewerenondingsinthisstudywhichwouldprecludeadministeringthiscompoundtomalariapatients.
TheresultsofpreclinicalstudiessuggestthatantimalarialefcacyofKAE609maybeAUCdriven.
(S.
B.
Lakshminarayana,C.
Freymond,C.
Fischli,etal.
,submittedforpublication).
BasedontheP.
bergheimousemodel,thedailydosesufcienttoclear99%oftheparasitesdetectedinthebloodwas5.
3mg/kg;exposure(AUC0–24)atthisdosewasestimatedtobe3,260ng·h/mlbasedonmodelingofpharmacokineticdataobtainedwithnoninfectedmice.
Allomet-ricscalingofmouse,rat,anddogpharmacokineticdatayieldedapredictedequivalenthumanefcaciousdoseof30mg(predictedAUC0–24of3,570ng·h/ml)fora70-kghuman.
Thehealthyvol-unteerpharmacokineticdatareportedhereareconsistentwiththesepredictionsandsuggestthata30-mgdailydosemightbeTABLE3SummaryofpharmacokineticparametersofKAE609followingoraladministrationofmultipleascendingdoses(part2)PharmacokineticparameterMeanSDfordosegrouponindicatedday10mg30mg60mg100mg150mgDay1Day3Day1Day3Day1Day3Day1Day3Day1Day3AUC0–24(g·h/ml)1.
240.
201.
910.
44.
080.
726.
421.
226.
990.
9714.
13.
4812.
21.
9419.
83.
5615.
12.
7329.
44.
12Cmax(ng/ml)12016.
716129.
336455.
446869.
264191.
79912169211641,1702061,1702601,770232Tmaxa(h)2(1.
0–3.
0)2(1.
0–2.
0)2(2.
0–2.
02)2(1.
0—2.
0)2(1.
0–4.
0)1.
5(1.
0–2.
0)3(1.
0–4.
0)2(2.
0–4.
0)2(2.
0–4.
0)2.
5(2.
0–8.
15)T1/2(h)NAb21.
44.
4NA22.
45.
0NA28.
04.
5NA23.
16.
1NA26.
98.
3Racc1.
541.
572.
011.
671.
98aValuesaremeansstandarddeviations,exceptforTmaxvalues,whicharemedians(withrangesshowninparentheses),andRaccvalues(forwhichonlythemeansarereported).
N6to7subjectspercohort.
bNA,notavailable;theT1/2wasdeterminedonday3only.
AntimalarialSpiroindoloneKAE609/CipargaminFIHStudyOctober2014Volume58Number10aac.
asm.
org6213onMarch24,2021byguesthttp://aac.
asm.
org/Downloadedfromsufcienttogeneratethemaximumparasitemiareductioninma-lariapatients.
Indeed,astudywhichfollowedthisstudydemon-stratedpositiveresultsin2013(16):a3-dayregimenof30mgdailyclearedparasitemiainP.
vivaxandP.
falciparummalariapatients.
ACKNOWLEDGMENTSThestudywassponsoredbyNovartis.
WegratefullyacknowledgethesignicantnancialcontributionsfromtheWellcomeTrustandMedi-cinesforMalariaVenturestotheNovartisInstituteforTropicalDiseasesdrugdiscoveryprogramandtheearlyclinicaldevelopmentofKAE609.
WeacknowledgetheworkofJoanneMarjasonandtheclinicalteamatQ-PharmPty.
Ltd.
,Brisbane,Australia.
Finally,wethankVikramGoudforprogrammingsupport.
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