等效与安全性：恩他卡朋双巴片与等量左旋多巴卡比多巴速释剂+恩他卡朋具有生物等效性

RobertA.Hauser,MD

Articleabstract—Alevodopa/carbidopa/entacaponecombinationproduct(Stalevo)wasrecentlyapprovedtotreatpa-tientswithidiopathicParkinson’sdisease(PD)whoexperienceend-of-dose“wearing-off.”Stalevoisavailableindosecombinationsoflevodopa/carbidopa/entacapone50/12.5/200mg(Stalevo50),100/25/200mg(Stalevo100),and150/37.5/200mg(Stalevo150).AseriesofpharmacokineticstudiesdemonstratedbioequivalencebetweenStalevoandcorrespond-ingdosagesoflevodopa/carbidopaplusentacapone.AclinicaladvantageofStalevoisthatpatientscantakeonepillratherthantwo(ormore)separatetablets.Inaddition,Stalevo50and100tabletsaresmallerthanentacaponetablets.Theseadvantagesmaybeparticularlybeneficialforpatientstakingmanypills,thosewhohavedifficultyfollowingcomplexmedicationregimens,andthosewithswallowingdifficulty.MostPDpatientstakinglevodopa/carbidopaimmediate-release(IR)plusentacaponecanbedirectlyswitchedtothecorrespondingdoseStalevoproduct.ForfluctuatingPDpatientstakinglevodopa/carbidopaIRwithoutentacapone,switchingtothecorrespondingStalevotabletisanalogoustoaddingentacapone.Inswitchingpatientswhoarereceivinglevodopa/carbidopacontrolled-release(CR),itshouldbenotedthatthebioavailabilityoflevodopafromlevodopa/carbidopaCRisapproximately70–75%thatoflevodopa/carbidopaIRproducts,includingStalevo.

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Whenlevodopaisadministeredwithadopadecar-boxylaseinhibitor(DDI),suchascarbidopaorbenserazide,thepredominantrouteoflevodopame-tabolismisviacatechol-O-methyltransferase(COMT)toform3-O-methyldopa(3-OMD).Entaca-poneisaselective,reversible,peripherallyactingCOMTinhibitorthatincreasesthelevodopahalf-lifeandconcentrationareaunderthecurve(AUC).1Thismakesmorelevodopaavailablefortransportintothebrainoveralongertime.When200mgentacaponeisadministeredwithlevodopa/carbidopaimmediatere-lease(IR),thelevodopaAUCisincreasedby35–40%andthehalf-lifeisprolongedfrom1.3to2.4hours.2-4InclinicaltrialsofPDpatientswithmotorfluctua-tionsreceivinglevodopa/DDI,theadditionofentaca-poneincreased“on”time,decreased“off”time,improvedparkinsonianmotorstatus,anddecreasedtheaveragedailylevodopadose.5-8Rationaleforacombinationproduct.Entaca-poneisrapidlyabsorbedafteroraladministrationandhasaneliminationhalf-lifeofapproximately0.4–0.7hours.4,9LevodopaadministeredwithaDDIisalsorapidlyabsorbedandhasaneliminationhalf-lifeofapproximately1.25hours.3Becauseoftheirsimilarpharmacokineticprofiles,entacaponeandlevodopa/DDIareroutinelyadministeredtogetherinclinicalpractice.Acombinationproductshouldpro-videthesamepharmacokineticprofileandclinicaleffectsaslevodopa/DDIplusentacaponetakento-gether,whileaffordinggreaterconvenience.IntheUnitedStates,thecombinationproductoflevodopa,carbidopa,andentacaponeisgenericallyreferredtoascarbidopa/levodopa/entacapone,whereasintheEuropeanUnionitislevodopa/carbidopa/entacapone.Forsimplicity,thecombinationproductofthesethreedrugswillbereferredtoherebyitstradename,Stalevo.

Stalevoofferstheclinicalbenefitsthatareob-tainedwhenentacaponeisaddedtolevodopa/carbi-dopa.Inaddition,Stalevoofferstheincreasedconvenienceoftakingonlyonetabletinplaceoftwo(ormore),andtheavailabledosecombinationsallowmoresubtlelevodopatitrationwithouttheneedtosplittablets.Stalevoisavailableaslevodopa/carbi-dopa/entacapone50/12.5/200mg(Stalevo50),100/25/200mg(Stalevo100),and150/37.5/200(Stalevo150).Theseadvantagesareparticularlydesirableforpatientstakingmanypillseachdayandthosewhomayinadvertentlymixupmedicationsorhavediffi-cultyadheringtocomplextreatmentregimens.Byensuringthesimultaneousadministrationoflevo-dopa/carbidopaandentacapone,thecombinationpillsimplifiestherapyandsupportstheproperuseofentacapone.AnadditionaladvantageisthatStalevo50and100tabletsaresmallerthanentacaponetab-lets.Thismaybeparticularlyrelevantforpatientswithswallowingdifficulties.Thereisalsoconsider-ableinterestinthepotentialofentacaponetoreducethepulsatilityoflevodopabecauseitprolongslevo-dopa’sotherwiseshorthalf-lifeandmaytherebyre-ducetheriskforinductionofmotorcomplications(seearticlebyOlanowinthissupplement).Ifthishypothesiscanbesubstantiatedinclinicaltrials,theintroductionofStalevowillsimplifyadministration

FromtheDepartmentsofNeurology,Pharmacology,andExperimentalTherapeutics,UniversityofSouthFloridaandTampaGeneralHealthcare,Tampa,Florida.

PublicationofthissupplementwassupportedbyanunrestrictededucationalgrantfromNovartisPharmaAGandOrionCorporation,OrionPharma.

AddresscorrespondenceandreprintrequeststoDr.RobertA.Hauser,Parkinson’sDiseaseandMovementDisordersCenter,UniversityofSouthFlorida,4ColumbiaDrive,Suite410,Tampa,FL33606.S

Copyright©2004byAANEnterprises,Inc.

Table1Demographiccharacteristics(mean,range)ofhealthyvolunteersinthebioequivalencestudiesofStalevo17Stalevo100StudyNo.NGender(m/f)Age(yrs)N(Ͻ55yrs)N(55–59yrs)N(60–65yrs)N(Ͼ65yrs)Weight(kg)Height(cm)Nϭnumberofsubjects.

BE-100A4444/024(20–38)44ϪϪϪ73(63–85)181(171–192)BE-100B4417/2759(45–72)147101370(53–85)169(156–183)Stalevo50BE-504423/2158(45–75)171010773(50–99)170(155–188)Stalevo150BE-1504424/2058(45–74)161112577(52–98)172(155–190)andenhancethebenefitsoflevodopafromthetimeitisfirstemployed.

Pharmacokineticstudies.ThedevelopmentandregistrationprogramsforStalevowerebasedmainlyondemonstrationsofbioequivalencetolevodopa/carbidopaplusentacaponeadministeredsimulta-neously.ThesebioequivalencestudieswereconductedwiththeStalevoformulationstobemar-keted.Thereferenceproductwaslevodopa/carbidopaIR(Sinemet)100/25mgtabletsindosagesof50/12.5mg(halftablet),100/25mg(onetablet),and150/37.5(oneandahalftablets)administeredwithentaca-pone(Comtess*)200mg.

Fourbioequivalencestudieswereconducted.Thefirststudy(BE-100A)wasperformedin44healthyyoungmalevolunteersandevaluatedStalevo100.Threesubsequentstudies(BE-50,BE-100B,andBE-150)evaluatedStalevo50,100,and150in44maleorfemalevolunteers(perstudy)45to75yearsofage,arangeapproximatelycomparabletothatofthePDpatientpopulation.Thesestudiesusedanopen,randomized,crossoverandreplicatedesignwithtwosequences:testversusreferenceversustestversusreference,orreverseorder.Onevaluationdays,asingledoseofthetest(Stalevo)orreferenceproducts(Sinemetplusentacapone)wasadministeredafteranovernightfast,andbloodsampleswerecollectedbeforedosing(0minutes),at10,20,30,45,60,75,and90minutes,andat2,3,4,5,6,8,10,and12hoursafterdrugadministration.Plasmaconcentra-tionsoflevodopa,carbidopa,andentacaponeweredeterminedbyhigh-performanceliquidchromatogra-phywithelectrochemicaldetection(HPLC-EC).Fortheevaluationofbioequivalencebetweentestandreferences,theareaundertheconcentration–timecurvefromzerotoupto12hours(AUC0–12hrs),thepeakconcentration(Cmax),thetimetoreachpeakconcentration(tmax),andtheeliminationhalf-life(t1/2)forlevodopa,carbidopa,andentacaponewere

*ComtessandComtanaretradenamesforentacapone.

determined.The90%confidenceintervals(CI)fortheratio(test:referencetreatment)ofthegeometricmeanswerecalculatedandbioequivalencewaseval-uatedusingpredefinedacceptancecriteria.

Safetywasevaluatedduringeachstudybymea-surementofvitalsigns(bloodpressure,heartrate,andbodytemperature)andrecordingECGsbeforedosingandduringthestudydays.Inaddition,labo-ratoryassessments,ECGs,andvitalsignmeasure-mentswereperformedatthepre-andpost-studyexaminationsandadverseeventswererecordedthroughoutthestudies.Safetywasevaluatedusingdescriptivestatisticsforvitalsignsandtheirchangesduringthestudy.Forlaboratorysafetyvari-ables,descriptivestatisticsandthechangebetweenthepre-andpost-studyvisitswereevaluated.

Demographiccharacteristicsofthesubjectsineachstudyarepresentedintable1.Thirty-nineto42subjectscompletedeachstudy.Equivalencecrite-riaweremetforallthreecomponents(levodopa,car-bidopa,andentacapone)ofallthreeStalevodoseformulations.Themeanconcentration–timecurvesforlevodopa,carbidopa,andentacaponewithStalevo50,100,and150,andthereferencetreatmentsarepresentedinfigure1.ThemeanAUCandCmaxval-uesforlevodopa,carbidopa,andentacaponeforalltestandreferencedosagesarepresentedintable2.SomevariabilityinentacaponeCmaxwasnotedbutitremainedwithinacceptablelimits.The90%CIsfortheratioofthegeometricmeans(test/referencetreatment)oflevodopaAUCandCmaxvaluesareshowninfigure2,illustratingbioequivalencebe-tweentestandreferencetreatments.Meanlevodopahalf-lives(t1/2)wereequalfortestandreferenceproductswithineachstudyandacrossallfourstud-ies.ForStalevo,themeanlevodopahalf-lifewas1.7hourswitharangeof1.2–3.1hours.

Nodeathsorseriousadverseeventsoccurredinthesestudies,andsafetymeasureswerenotsignifi-cantlydifferentfortestandreferenceproducts.The

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Figure2.Ratioofgeometricmeansand90%CIsofAUCandCmaxvaluesoflevodopafordifferentStalevodosagesandthereferencetreatmentsinolderhealthyindividu-als.17Figure1.Meanconcentration–timecurvesfor(A)levo-dopa,(B)carbidopa,and(C)entacaponeinbioequivalencestudies17morefrequentlywithStalevo150thanwiththecor-respondingreferenceproducts.

InstudyBE-150,nausea,atypicaldopaminergicsideeffectthatoccursparticularlywhenlevodopaisadministeredtohealthyvolunteers,wasreportedby13subjectsafterthetestproduct(Stalevo)andsixsubjectsafterthereferenceproducts(Sinemetplusentacapone).Inprevioussmallentacaponestudiestherewasnodoserelationshipwithtolerabilitywhenentacaponewasgivenwithoutlevodopainsin-gledosesfrom25to800mg9orwhenentacaponewasgiventogetherwithlevodopaindosesfrom50to400mg.10Similarly,therewerenodose-relateddif-ferencesintheoccurrenceofadverseeventswhenentacaponewasadministeredrepeatedlyatdosesof100,200,and400mguptosixtimesdailyinPDpatientswithmotorfluctuationsonlevodopa.11How-ever,inlargedouble-blindclinicaltrialsofPDpa-tientswithmotorfluctuationsonlevodopa,theincidenceofnauseawassignificantlyhigherinthoserandomizedtoadjunctiveentacaponethantoplace-bo.5,6Itisthereforepossiblethatthehigherinci-denceofnauseaobservedwithStalevo150comparedwiththereferenceproductsrelatestothehighermeanentacaponeCmaxobservedinthisstudy.How-ever,furtherinvestigationdidnotidentifyanyrela-tionshipbetweennauseaandplasmaconcentrationsoflevodopa,carbidopa,orentacapone(eitheratthetimeoftheeventorduringtheday)comparedwiththeconcentrationsinotherperiodsorwiththoseinsubjectswhodidnotreportnausea.Itisthereforedifficulttodrawanyfirmconclusionsastothecauseoftheincreasedincidenceofnauseaseeninthisstudy.

PracticaluseofStalevo.StalevoisindicatedfortreatpatientswithidiopathicPDwhoarebeingtreatedwithlevodopaandexperiencingthesignsandsymptomsofend-of-dosewearing-off.Becausethemaximalrecommendeddailydoseofentacaponeis1600mg/dayintheUnitedStatesand2000mg/dayintheEuropeanUnion,themaximaldailylevo-

mostcommonlyreportedadverseeventswerehead-ache,nausea,upperrespiratorytractinfection,andfatigue(table3).Therewerenosignificantdiffer-encesintheadverseeventprofilesbetweentestandreferenceproducts,exceptthatnauseawasobserved

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Table2AUC(hϫng/ml)andCmax(ng/ml)forlevodopa,carbidopa,andentacaponeinthebioequivalencestudiesforStalevo50,100,and150inolderhealthyindividuals17

AUC*(meanϮSD)

StrengthStalevo50

LevodopaCarbidopaEntacapone

Stalevo100

LevodopaCarbidopaEntacapone

Stalevo150

LevodopaCarbidopaEntacapone

Stalevo998Ϯ310150Ϯ1249Ϯ5222840Ϯ697633Ϯ2111439Ϯ3773717Ϯ1101488Ϯ1801233Ϯ373

Reference†970Ϯ287150Ϯ561255Ϯ4242745Ϯ7085Ϯ2201383Ϯ3573824Ϯ1116551Ϯ1921216Ϯ440

Cmax(meanϮSD)

Stalevo473Ϯ139Ϯ161199Ϯ884975Ϯ247125Ϯ421259Ϯ7121272Ϯ329107Ϯ421211Ϯ738

Reference†4Ϯ15339Ϯ141152Ϯ5581036Ϯ308126Ϯ421070Ϯ4601384Ϯ445121Ϯ451052Ϯ792

*AUC0–10hforStalevo50andStalevo100andAUC0–12hforStalevo150.

†Standardreleaselevodopa/carbidopa(Sinemet)andentacapone200mgtablet(Comtess).

dopadosethatcanbeadministeredbyStalevoaloneis1200mg/day(Stalevo150ϫ8)intheUnitedStatesand1500mg/day(Stalevo150ϫ10)intheEuropeanUnion.Stalevowillmostcommonlybein-troducedinthreeclinicalcircumstances:switchingfromlevodopa/carbidopaIRplusentacapone,switch-ingfromlevodopa/carbidopaCRplusentacapone,andswitchingfromlevodopa/carbidopaformulationsalone.

Patientsreceivinglevodopa/carbidopaIRplusen-tacaponecanbeswitcheddirectlytothecorresponding-doseStalevotabletifsuchadosecom-binationisavailable.PatientsintheEuropeanUniontakinglevodopa/benserazidewithentacaponewillsimilarlybeabletoswitchdirectlytoStalevo.Toestimatetheproportionofpatientsreceivinglevo-Table3Adverseevents(Ͼ2%frequency)reportedinStalevobioequivalencestudies

Test(Stalevo)(Nϭ176)

AdverseeventHeadacheNausea

UpperrespiratorytractinfectionFatigueVomitingDizzinessDiarrheaRhinitis

Influenza-likesymptomsBackpainPharyngitis

Nϭnumberofsubjects.

N412513978653

%23.314.27.45.14.04.53.42.82.82.31.7

Reference(Nϭ176)N3415955744124

%19.38.55.12.82.84.02.32.30.61.12.3dopadosesthatcorrespondtolevodopadosesavail-ableinStalevotablets,ananalysiswasundertakenofindividuallevodopadosesintwoPhaseIIIentaca-poneclinicaltrialsofPDpatientswithmotorfluctu-ations.5,6Inthesestudies,approximately50%oftheindividualbaselinelevodopadoseswere100mg,andanother30%were50or150mg.Therefore,approxi-mately80%oflevodopaintakesconsistedofoneofthesethreelevodopadoses.Additionalanalysisre-vealedthatapproximately80%ofpatientsweretak-ingtotaldailylevodopadosagesoflessthan1000mg/dayatbaseline.

Anotherpotentialconsiderationisthelevodopa:carbidoparatio.TheStalevolevodopa:carbidopara-tiois4:1,whereasotherlevodopa/carbidopaproductsareavailableinboth4:1and10:1doseratios.Thedailycarbidopadoserequiredtosaturateperipheraldopadecarboxylaseandtherebymaximizeclinicalresponseandminimizenauseaisatleast70to75mg/day.12-14Thisismorereadilyaccomplishedusingthe4:1ratioandtheseproductsarethereforemorecommonlyusedinclinicalpractice.IntheSEESAWstudy,6morethan70%ofpatientsweretaking4:1ratioproductsexclusively.Anadditionalpharmaco-kineticstudywasconductedtoevaluateswitchingfromlevodopa/carbidopaIRproductswitheithera10:1or4:1ratiotoStalevo.TheprincipalfindingofthisstudywasthatswitchingtoStalevosimilarlyincreasedthelevodopaAUC,irrespectiveoftheini-tiallevodopa:carbidoparatio.

ItisalsopossibletoswitchfluctuatingPDpa-tientsreceivinglevodopa/carbidopaCRplusentaca-ponetoStalevo.Thebioavailabilityoflevodopafromlevodopa/carbidopaCRisapproximately70to75%thatoflevodopa/carbidopaIR.15ThismeansthatthelevodopaAUCproducedbylevodopa/carbidopaCR200/50plusentacapone200mgshouldbeapproxi-matelycomparabletoStalevo150.However,thelevodopaabsorptionprofilesforStalevoandlevo-dopa/carbidopaCRaredifferent.LevodopafromSta-January2004

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Table4Percentageofpatientsdecreasingdailylevodopadoseby4–6weeksafterentacaponeinitiationinPhaseIIIclinicaltrialsasgroupedbybaselinedailylevodopadoseandpresenceofdyskinesia5-8

LevodopaϽ600mg/day(Nϭ180)

Nodyskinesia(Nϭ159)Dyskinesiapresent(Nϭ279)

4%31%

Levodopa600–800mg/day(Nϭ153)

21%43%

LevodopaϾ800mg/day(Nϭ105)

28%66%

levohasatmaxsimilartothatoflevodopa/carbidopaIR(0.5–1.5hours),whereasabsorptionismorede-layedfromlevodopa/carbidopaCR(tmax1.5–3hours).15Thesedifferencesshouldbeconsideredwhenpatientsareswitchedfromlevodopa/carbidopaCRtoStalevo.Ingeneral,ashorterlevodopatmaxisdesirableinpatientswithmotorfluctuationstomin-imizethetimefrommedicationadministrationtoonsetofclinicaleffect.

Notalllevodopa/carbidopaplusentacaponeregi-menscanbeeasilyconvertedtoStalevo.PatientsreceivingindividuallevodopaIRdosesof200mgormorewithentacaponehavenocorrespondingdoseoptionwithStalevo.Inaddition,themaximalrecom-mendeddailydoseoflevodopafromStalevoaloneis1200mgintheUnitedStatesand1500mgintheEuropeanUnionduetolimitedexperiencewithenta-caponedailydosesabove1600mg/dayintheUnitedStatesand2000mg/dayintheEuropeanUnion.Thesepatientscanbetreatedwithlevodopa/carbi-dopaplusentacaponeoracombinationofStalevoandlevodopa/carbidopaproducts.

ForPDpatientswithwearing-offwhoarereceiv-inglevodopa/carbidopabutnotentacapone,switch-ingtothecorrespondinglevodopa-doseStalevotabletshouldprovidethesameclinicalbenefitandside-effectprofileasaddingentacapone.However,inthisinstance,becauseentacaponecanincreasedopami-nergicadverseeffectssuchasdyskinesiathedailylevodopadosemayneedtobereduced.Thelikeli-hoodofalevodopadosereductioninthefourdouble-blindPhaseIIIentacaponestudies5-8ispresentedintables4and5.16Ofthesestudies,theNOMECOMT5(Nϭ171)andSEESAW6(Nϭ205)studiesincluded

Table5Absolutedailylevodopadosereduction(mg/day)by4–6weeksafterentacaponeinitiationinpatientswhodecreasedtheirlevodopadose5-8

LevodopaϽ600mg/day

NodyskinesiaDyskinesiapresent

Ϫ71(Nϭ6)Ϫ68(Nϭ39)

Levodopa600–800mg/dayϪ77(Nϭ11)Ϫ130(Nϭ)

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onlyfluctuatingPDpatients,whereasintheCE-LOMEN7(Nϭ301)andUK-IRISH8(Nϭ300)stud-ies,84%and57%ofthepatients,respectively,werefluctuatingbasedondiarydataobtainedbeforeran-domization.Analysisdemonstratedthatthepres-enceofdyskinesiasandhigherdailylevodopadoseatbaselinewereassociatedwithanincreasedlikeli-hoodoflevodopadosereductionafterentacaponeini-tiation(seetables4and5).Thepresenceofdyskinesiaswasastrongerpredictoroflevodopadosereductionthandailylevodopadose.Inthesestudies,themeandailylevodopadosereductionwasbetween40and100mg/daywiththeadditionofentacaponecomparedwithplacebo.Basedonthesedata,theFDArecommendsthatpatientsexperienc-ingpeak-dosedyskinesiasandthosereceivingadailylevodopadoseofmorethan600mg/dayshouldfirstbetitratedindividuallywithlevodopa/carbidopa(ratio4:1)andentacapone,andthenswitchedtoSta-levooncestabilized.

Forpatientswithend-of-dosewearing-offwithoutpeak-dosedyskinesias,entacaponeisusuallyaddedwithoutchangingthelevodopadose.Ifdopaminergicsideeffectsemerge,thelevodopadosecanbere-duced.Incontrast,oneshouldconsiderreductionofthelevodopadoseatthetimeentacaponeisaddedforpatientswithmoderateorseverepeak-dosedys-kinesias.Theseprinciplescanalsobeappliedtoswitchingfromlevodopa/carbidopaalonetoStalevo.Toachieveareductioninlevodopadose,alower-doseStalevotabletcanbeadministeredorthefrequencyofadministrationdecreased.

Conclusion.Stalevocanprovidethebenefitsoflevodopa/DDIplusentacaponewithgreaterconve-niencebyallowingtheadministrationoffewerpillsperday.PharmacokineticstudieshavedemonstratedbioequivalencebetweenStalevoandlevodopa/carbi-dopaIRplusentacapone.Mostpatientsnowreceiv-inglevodopa/carbidopaIRplusentacaponecanbeeasilyswitchedtothecorrespondingStalevotablets.Switchingfromlevodopa/carbidopaIRalonetothecorrespondingdoseStalevotabletisanalogoustoaddingentacapone.PatientsreceivingindividuallevodopaIRdosesof200mgandabove,andthosepatientsreceivingmorethan1200mg(US)or1500mg(EU)oflevodopa/daycanbetreatedwithlevo-dopa/carbidopaplusentacaponeoracombinationofStalevoandlevodopa/carbidopa.

Discussion

DR.POEWE:IwasconfusedbyonegraphinwhichyoushowedthatStalevo100haddifferentplasmalevelprofilesintwostudies.Itwasthesamedose,buttheprofileslookeddifferent.

DR.HAUSER:Yes.Thepopulationsweredifferent.YouarereferringtostudyBE-100A,whichwascon-ductedinhealthyyoungmalevolunteers,andstudy

LevodopaϾ800mg/dayϪ1(Nϭ14)Ϫ249(Nϭ)

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BE-100B,whichwasconductedinelderlymenandwomenwhoaremoreakintothePDpopulation.WhatyouseeisthatthehealthyyoungmenhavealowerAUCforlevodopathantheelderly.Theseagedifferenceshavealsobeenreportedwithotherlevo-dopa/carbidopaformulationsinotherstudies.DR.LEWITT:Whathasbeenshowninseveralstudiesisthatwithagethereisbetterlevodopaabsorption.Thismaybethereasonfortheobservationthatyoucanreducethelevodopadoseasthediseaseprogresses.Agingitselfimprovestheuptakeorbio-availabilityoflevodopa.Iamcuriousthatyoudidnotseemorenauseainthegroupwithlowercarbi-dopaintake.Thereisgoodevidencethattheminimalthresholdforoptimaldecarboxylaseinhibitionissomewherebetween50and75mgofintakeperday.ButpatientstakingStalevo50threetimesperdaywouldbebelowthatthresholdandIwouldhavepredictedanincreasedincidenceofnauseabecauseofinadequatecarbidopainthetriple-combinationproduct.SinceintheUnitedStateswedonothavereadyaccesstosupplementarycarbidopanow,thismaybecomeanissue.Ifsuchpatientsdevelopper-sistentnausea,oneshouldtrytogetmorecarbidopaintothatindividualinanywayonecan,usingthehigher-doseStalevoproductorsupplementalimmediate-releaselevodopa.Ithinkthisisapoten-tialproblemwiththelowdoseifitisusedbyitselfinpatientswhoaresusceptibletodopaminergicsys-temicsideeffectssuchasnausea.

DR.HAUSER:Ishouldmentionthatinthesestudiesitwasasingle-doseadministration,sothecarbidopawasjustthecarbidopaofonetablet,whichwouldobviouslybelessthanwhatyouwouldgetwiththreeorfouradministrationsperday.

DR.OLANOW:Weinitiallyrecommendedthatthemedicationbedevelopedwiththecarbidopaanden-tacaponedosesremainingconstantandchangesonlyinthelevodopadoseforthereasonyousay.How-ever,itwouldnothavebeenpossibletogetapprovalwithbioequivalenceusingthisapproach.Ithinkitisimportant,though,tomakesurethatpatientsun-derstandwhytheymightexperiencenauseaandhowtodealwithit.Increasingevidencesuggeststhatitisprobablynotagoodideatostartwithlevodopa50mgthreetimesperdaybecauseofthepotentialforlowtroughlevels,butmanyphysiciansusethisreg-imen.

DR.LEWITT:Ithinkthatisanissue,though,becausemanyphysiciansfollowthetheme“useaslittlelevo-dopaaspossible,”andmanyphysiciansmaybeat-tractedtothe50-mgtablet.

DR.POEWE:Wehavebeenusing50-mgdosesforthepastdecade.Areyousayingthisisaproblem?

DR.OLANOW:Therearetwoissueshere:first,thetotalamountofcarbidopathatisprescribed.Ifaphysiciantreatspatientswith50mgtwicedaily,theywillreceiveonly25mgofcarbidopa,whichmaynotbeenoughtoadequatelysuppressdecarboxylaseandtheymayexperiencenauseaandvomiting.Thisisprobablynotabigproblembecauseweoftenstartpatientsonhalftabletsandnauseaisnotsuchabigproblem.However,morethan80%oflevodopa/carbi-dopaisprescribedasthefull100/25tablet.IflargenumbersofpatientsareplacedontheStalevo50tablet,nauseaandvomitingmaybemoreofaprob-lem.Thesecondpointdealswiththeoreticalconsid-erations,indicatingthatpulsatilestimulationisassociatedwiththeinductionofmotorcomplicationsandrecentstudiessuggestingthatthisisprimarilyrelatedtoalterationsbetweenhighpeakandlowtroughlevels.Therefore,wesuspectthatitmaybebettertoavoidlowtroughs.Ontheotherhand,iflevodopaisdeliveredmorecontinuously,itisnotsuchaproblemtohaverelativelyhighlevodopacon-centrations.

DR.HAUSER:Iamnotparticularlyconcerned.Werou-tinelyintroducelevodopa/carbidopaathalfofa100/25tabletonceadayforaweek,followedbytwicedailyforaweek,followedbythreetimesperdayforaweek,andtheincidenceofnauseaisextremelylow.Soitseemstoworkwell,andbasedonbio-equivalenceitwillprobablydojustaswellwithSta-levo.

DR.POEWE:Ialsothinkthiswillnotbeaproblem.InEurope,Madoparhasbeenonthemarketforagesasa50-mglevodopa/12.5-mgbenserazideformulation,andmanyphysiciansusethisdosetostarttreat-ment.Withthisapproachnauseahasnotbeenaproblem,andIdon’tthinkitwillbewithStalevo50.DR.LEWITT:Youmayberight,butthereasonwegotawayfromthe100:10levodopa/carbidopaformula-tionandswitchedtothe100:25productwasstrictlybecauseofthehigheroccurrenceofnauseawiththelowercarbidopadose.

DR.BROOKS:Wealsoknowthatyouneedabout150mgofcarbidopaperdaytofullyblockdopadecarbox-ylase,andwerarelyachievethatlevelinpractice.DR.LEWITT:Inonestudy,250mgofcarbidopapro-vided94%inhibitionofdecarboxylase,sothereisalwayssomethatsneaksby.Givingmassiveamountsofinhibitordoes,however,improvethecon-sistencyofthelevodopaeffect.

DR.HAUSER:Inthevolunteerstudies,thehighestfrequencyofnauseawasseenwiththe150-mgtestandreferenceproducts.Thatwouldbeakintostart-January2004

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ingapatientononeandahalftabletslevodopa/carbidopa100/25,whereasinclinicalpracticewetypicallystartwithhalfofa100/25tableteachday.Soitisnotsurprisingthattherewasnauseawiththisdose.ThebiggestdifferencebetweengroupswaswiththeStalevo150tablets,whichwereassociatedwithahigherCmaxofentacaponeinthetriple-combinationgroup.Itmaybethatthehigherinci-denceofnausearelatestothishigherconcentrationofentacapone.

DR.REINIKAINEN:Idonotbelievethatentacaponecausesnauseabecausewefoundnodifferenceinthefrequencyofthisadverseeffectinsingledose-findingstudieswithdosesupto800mg.Infact,wegaveentacaponetohealthyvolunteersindosesupto2400mgperdayfor10days,andtherewasnodifferencefromplacebowithrespecttonausea.ItispossiblethatcarbidopaitselfcouldcausethenauseainsomeoftheStalevostudies,buttheredidnotseemtobeanycorrelationwhenweperformedtheseanalyses.SoIbelievethedifferenceinnauseabetweengroupswasjustchanceandisnotclinicallyrelevant.DR.OLANOW:Thereisanotherpointthatneedstoberaised,andthatishowlittleinformationthereisavailablewithStalevoinPDpatients.Iknowthereareseveralstudiesongoingandpreliminaryresultsshowthatitisusuallyeasytoswitchpatientswhoarealreadyonentacaponeandlevodopa/carbidopaasseparateproducts,andthosewhoaretakinglevo-dopa/carbidopaalone.Ingeneral,itiswelltolerated,UPDRSscorestendtobeimproved,andpatientsgenerallylikeitbecauseoftheconvenienceandeaseofadministration.Afewpatientswithdyskinesianotedenhanceddyskinesiabutthiswaseasilytreatedbyloweringthedose.

IalsopersonallythinkthatthebestroleforSta-levowillbeinearlypatientsasameansofprovidingthebenefitsoftraditionallevodopawithareducedriskformotorcomplications.Thisneedstobeprovedinclinicaltrials,butpreliminarystudiesinmonkeyssupportthishypothesis.Inthesepatients,thetriple-combinationproductwillbeespeciallyeasytouse—youjuststartitaswithlevodopaandtitratetothecorrectdose.Forthisreason,Iwouldsuggestthatastudythatshouldbedone,inadditiontotheswitch-ingstudy,isoneinearlyPDpatientswhohavenotyetbeentreatedwithlevodopatotestitsantiparkin-sonianefficacyandtolerabilityinthispopulation.DR.STOCCHI:IagreeentirelywithDr.Olanow’scom-ments.Firstofall,patientswithPDhaveahighertolerancetodopaminergicdrugsthanthestandardnormalpopulation.The50-mglevodopadoseiscom-monlyusedinourcountrytostarttreatment,asDr.Poewesaid,andwerarelyhaveaproblemwithnau-sea.ItispossiblethatnauseawasseenintheearlyPKtrialsbecauseofthelargerlevodopadosethat

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wasemployed,andmayrepresentacentraleffect.Isaythisbecauseinmanyofthesecasestheydonotrespondwelltotheperipheraldopamineantagonist,domperidone,whereastheydorespondifyouusecentralantidopaminergicdrugs.Sonauseamightbeacentraleffectduetotheamountofdopamine,morethanjustaperipheralgastriceffect.Idonotthinkthiswillbeaprobleminpatientswhoquicklyde-veloptolerancetonausea.

DR.REINIKAINEN:Inourdatabase,wecomparedthefrequencyofnauseainpatientsonthe4:1and10:1levodopa:carbidoparatios.Nauseawasreportedin29%ofpatientswiththe10:1ratiowhoreceivedlesscarbi-dopaandin15%ofpatientswhowerereceivinglevo-dopa:carbidopaina4:1ratio.Soitappearsthatwhenentacaponeisaddeditisbettertoleratedinpatientswhoareonlevodopa:carbidopawitha4:1ratio.DR.OLANOW:Dr.Hauser,earlieryoumadethepointthatentacapone,byblockingCOMT,mightpromotetheperipheralconversionoflevodopatodopaminethatmightberesponsibleforthenausea.Doyouthinkthatadditionalinhibitionofdecarboxylasemightpreventthisfromhappening?

DR.HAUSER:Iwouldanticipatethatifwecanmain-tainfulldopadecarboxylaseinhibitiondespitead-ministrationofCOMTinhibition,itwouldpreventthat.HoweasilythatisachievedIamnotsure,butIthinkthisissomethingworthlookinginto.Theques-tioniswhatisactuallycausingthenausea,andthemostobviousanswertomeisthatitisduetoperiph-eraldopamineproduction.OneofthethingsIhavebeendoinginpatientswhogetnauseawithCOMTinhibitiontherapyisaddingmorecarbidopa,anditseemstohelp.

DR.OLANOW:Whichiswhatyouwoulddowithlevodopa-inducednauseaanyway.

DR.HAUSER:Right.Butitwouldnothelpifitwerejustentacaponesomehowcausingadirectnauseaeffect.DR.OLANOW:Iseewhatyouaresaying.Wehavespentalotoftimetalkingaboutnauseaandvomit-ingbasedontheseentacaponestudies.TherealityisthatinroutinepracticeIdonotrecallseeingthatmuchnauseaandvomitinginentacapone-treatedpatients,andthinkitisanon-issueforthemostpart.Isthatnotyourclinicalexperience?

DR.HAUSER:Ithinkthereareaverysmallminorityofpatientswhohaveanissuewithnausea.Again,I

thinkclinicalpracticesuggeststhatoneshouldstartatalowdoseofthe4:1ratioandslowlybuilditup.Ifpatientshavenausea,theyusuallydeveloptoleranceiftheyaremaintainedonthelowdoseandthenitcanbefurtherincreased.Ifnauseapersists,theycantakelevodopawithmealsoraddmorecarbidopaordomperidoneifavailable.Withthosefewsteps,somewherearound99%ofpatientsarereadilytreatedwiththeselevodopaformulations.

DR.OLANOW:Idonotdisagreewithhowtomanagethenauseaandvomiting,butwhatIamquestioningiswhethertheentacaponeisdoinganythingmorethanwhatjustalittlebitmorelevodopawoulddo,andmypointisthatitisaveryuncommoncomplica-tion.Ithinkyouhavepickeditupinstudieswhereitmaybetransientandmild,whichishowwesome-timesseeitinpractice,anditisstickingoutbecauseitisarelativelyhighnumber.Butinpracticalcon-siderations,Ithinkitisprobablygoingtobenodifferentfromwhatweseewithroutinelevodopa,whenifyouseenauseaandvomitingyoufollowpre-ciselythestepsyouhavejustoutlinedandthereisnoproblem.Ithasnotbeenmyexperiencethatenta-caponehasmeaningfullychangedthatpresentation.DR.OBESO:Ibasicallyagree.Idofeelthatthereisaverysmallproportionofpatientswhohaveanidio-syncraticsensitivitytoentacaponeandhavepersis-tentnauseathatappearstoberelatedtotheentacaponeandnotjustthelevodopa.

DR.LEWITT:Whywasasustained-releaseformula-tionoflevodopa/carbidopanotusedinthetriplecom-bination?

DR.REINIKAINEN:Firstofall,entacaponehasbeendemonstratedtobeeffectivewhenusedwithstandard-releaselevodopaformulations.Second,en-tacaponemorecloselymirrorsthepharmacokineticsoftheregularformulationoflevodopa/carbidopa.Thecontrolled-releaseformulationhasproblemswither-

raticabsorptionanddelayeduptake,whichmakeitlessdesirable.Forthesereasons,Ithinkitmadesensetodevelopthetriple-combinationpillwithen-tacaponeaddedtothestandardformulationoflevo-dopa/carbidopa.References

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