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OriginalManuscript
ClinicalPharmacology
Single-andMultiple-DoseinDrugDevelopment
2021,0(0)1–16
Pharmacokineticsand©2021ProtagonistTherapeuticsInc.
ClinicalPharmacologyinDrug
DevelopmentpublishedbyWiley
PharmacodynamicsofPN-943,PeriodicalsLLConbehalfofAmerican
CollegeofClinicalPharmacology
DOI:
aGastrointestinal-RestrictedOral
PeptideAntagonistofα4β7,
inHealthyVolunteers
,XiaoliCheng,LarryMattheakis,Ching-ChangHwang,RoyaNawabi,
DavidLiu,andSuneelGupta
Abstract
PN-943isanorallystable,gastrointestinal-restrictedpeptidethatbindsspeciicallytoα4ß7integrinonleukocytes,
blockingleukocytetrafickingtoandactivationinthegut,inhibitingcoloninlammationandreducingsignsandsymptoms
1wasairst-in-humanstudywith40malesubjectsreceivingPN-943,100to1400mgorplacebo,assingledosesand
57malesubjectsreceivingPN-943,100to1000mgorplacebo,,crossover
studycomparingmultipledosesof450-mgPN-943twicedailyasaliquidsolutionandasanimmediate-releasetabletin
--
restrictednatureofthepeptide,systemicexposurewasminimal;therewasanapproximatedose-proportionalincreasein
areaundertheplasmaconcentration–-dailydosingandanabsence
oftime--943afterahigh-fatmealreducedpeakplasma
concentrationandareaundertheplasmaconcentration–(<%)urinaryexcretionof
intactdrug,andtherewasadose-relatedincreaseinfecalexcretionofintactPN--dependentincreasesinblood
receptoroccupancyandreductioninbloodreceptorexpressionwereobserved,-
dailydosingresultedinsustainedreceptoroccupancywithlowplasmaluctuations(143%).PN-943wasgenerallywell
-dailydosingresultedinsustained
pharmacokineticsandpharmacodynamics,supportingfurtherinvestigationineficacystudies.
Keywords
α4β7antagonist,gastrointestinalrestricted,pharmacokinetics,pharmacodynamics,PN-943
Ulcerativecolitisisachronicinlammatoryboweldis-
easewitharemittingandrelapsingcourse,charac-
terizedbybloodydiarrhea,abdominalcramps,and
,2ThepathogenesisisthoughttoresultfromProtagonistTherapeutics,Inc,Newark,California,USA
inappropriateimmuneresponsetogastrointestinalThisisanopenaccessarticleunderthetermsoftheCreative
antigensandenvironmentaltriggersingeneticallysus-CommonsAttribution-NonCommercial-NoDerivsLicense,whichper-
3mitsuseanddistributioninanymedium,providedtheoriginalworkis
,theuseisnon-commercialandnomodiicationsoradap-
inEurope(505per100000persons)andNorthAmer-tationsaremade.
ica(249per100000persons).4Ulcerativecolitishasa
signiicantnegativeimpactonpatientqualityoflifeandSubmittedforpublication5December2020;accepted7March2021.
:
,PhD,MBA,ProtagonistTherapeutics,Inc,7707Gateway
corticosteroids,5-aminosalicylates,andimmunosup-Blvd,Suite140,Newark,CA94560
pressants,andmorerecentlywiththeuseofbiologics(e-mail:n.******@ptgx-):.
2ClinicalPharmacologyinDrugDevelopment2021,0(0)
Therapeuticoptionsforthelong-termmaintenanceto≥1conventionaltreatments,suchassteroids,im-
-munosuppressiveagents,–24Due
Aminosalicylatessuchassulfasalazine,olsalazine,bal-totheinconvenienceandpotentialsystemicrisksofin-
salazide,andvariousformsofmesalamineareeffectivejectabletreatments,anoral,gastrointestinal-restricted
onlyinmildtomoderatedisease,whereaspatientswiththerapeuticthatselectivelytargetstheα4β7integrin
-
(TNF)-α(eg,inliximab,adalimumab,golimumab,andPTG-100,airst-generationα4β7integrinantagonist,
certolizumab)–10Agentstargetedhavedemonstrateddose-dependentmucosalhealing
againstothercytokinesinvolvedintheinlammatorysuggestingthatanoral,gut-restricted,α4β7integrin
responsesuchasustekinumabagainstinterleukin(IL)--
12/IL-23,andtofacitinib,apan–Januskinase(JAK)943isanorallystablepeptideandastructuralanalog
inhibitor,arenowpartofthetherapeuticoptionsavail-ofPTG-100thatbindsspeciicallytotheα4β7integrin
ableforinlammatoryboweldisease,andseveralIL-23onleukocyteswithahigherinvitropotencythan
andsphingosine-1-phosphatereceptormodulatorsarePTG--943
–13hasminimalsystemicabsorption(<1%)inanimals
Inspiteofthewidearrayoftherapeuticoptions,andismoreeffectivethanPTG-100asmeasuredby
therearestilllimitationsinthetreatmentofinlam-greaterlevelsoftargetengagementandeffectsonT-cell
matoryboweldiseases,–induced
-αinhibitorsareineffectiveincolitisratmodel,PN-943dosingcausedasigniicantly
approximatelyone-ifthtoone-thirdofthepatients,lowermeancolonhistopathologyscorecomparedto
and10%to15%oftreatedpatientswhoshowanini-ratstreatedwithvehicleorPTG-
,14–16Cuta-blockadeofleukocytetrafickinginthegutandlocal
neousreactionsarealsothemostcommonadverselymphocyteactivation,27PN-943mayinhibitcolon
reactionswithanti--inlammation,reducingthesignsandsymptomsof
jectionsitereactions,cutaneousinfections,immune-
mediatedcomplicationssuchaspsoriasisandlupus-safety,tolerability,pharmacokinetics,andpharmaco-
likesyndrome,and,rarely,-943inhealthymalesubjects.
increasetheriskofinfectionandmayincreasethe
increasingrecognitionthatmitigationofthelocalin-Methods
-StudyDesign
isteredbudesonideand5-aminosalicylatesareeffectiveTwostudieswereconductedatasingleclinicalcenter
locally,andvariousotherlocallyactingagents,includ-(NucleusNetwork,Melbourne,Australia).Study1was
ingAMT-101,anoralbiologicfusionproteinofin-a3-partirst-in-humanstudyinhealthymalevolunteers
terleukin10,18TD-1473,aJAKinhibitor,19GB004,toassessthesafety,tolerability,pharmacokinetics,and
ahydroxylaseinhibitor,20andBT-11,alanthioninepharmacodynamicsofaliquidsolutionformulationof
synthetaseinhibitor,21haveshownpromiseorareun-PN-,placebo-controlled,
dergoingclinicalinvestigationforinlammatoryboweldouble-blindstudyofsingleascendingdosesofPN-943
allowhigherdosesofdrugtobedeliveredtothetargetescalationproceededfrom100mgto300mg,1000mg,
-mgdosecohortre-
Theα4β7integrin,presentonthecellsurfaceofceivedtreatmentinthefastedstateon1occasionand
circulatingmemoryTandBlymphocytes,isprimar-followingahigh-fatmealonasecondoccasionina
ilyinvolvedintherecruitmentofleukocytestothegas--fatmealconsistedof2eggs
,2stripsofbacon,2slicesoftoastwith
Themajorligandforα4β7,mucosaladdressincellad-butter,4ouncesofhashbrownpotatoes,and240mL
hesionmolecule,isselectivelyexpressedontheendothe-,subjectsrefrainedfrom
liumofthegastrointestinalvasculatureandispresentinfoodanddrinkexceptwaterfor10hoursbeforeand
Vedolizumabisanintravenouslyadministeredhu-inthe300-mgdosecohortduringthefedtreatment.
manizedimmunoglobulinGmonoclonalantibodyPart2wasarandomized,placebo-controlled,double-
directedagainstα4β7thathasbeenapprovedfortheblindmultiple-ascending-dosestudyin50malesub-
:.
Modietal3
once-dailydosingofPN--
Dosesevaluatedinpart2included100mg,300mg,andrationofthestudyandfor90daysafterthelastdose.
,twocohortsofsubjects(100Subjectswereexcludediftheyhadahistoryofclin-
mgand300mg)receivedfoodapproximately30min-icallysigniicantendocrine,gastrointestinal,cardiovas-
utesbeforeeachdoseandanother2cohortsofsubjectscular,hematologic,hepatic,immunologic,renal,respi-
(300mgand1000mg)refrainedfromfoodfor10hoursratory,orgenitourinaryabnormalitiesordiseases,or
-hadclinicallysigniicantlaboratoryabnormalities,in-
hortof9subjectsinpart2received300mgofPN-943cludingimpairedrenalfunction(serumcreatinine>106
inacrossoverfashiontoevaluatetheeffectofmealtim-μmol/Lorestimatedcreatinineclearance<80mL/min)
ingonthepharmacokineticsandpharmacodynamicsoralanineaminotransferaseoraspartateaminotrans-
ofPN-,ferasevalues>.
60,or90minutesafterPN-
open-label,randomized,crossovermultiple-dosecom-Procedures
parisonof900-mgonce-dailyand450-mgtwice--andmultiple-ascending-dose
dosingofPN--phaseofthestudyconsistedofsequentialdoseesca-
andfor1hourafterdosingofPN--943ormatchingplaceboas
Thesecondstudywasa5-daymultiple-dosepharma-a60-mLoralsolutioninaratioof8:
cokineticandpharmacodynamicstudycomparingtheforpharmacokineticswerecollectedbeforedosingand
liquidformulationandatabletformulationadminis-
teredas450mgPN-943twicedailyinhealthymaleandmultiple-ascending-dosephase,bloodsampleswereob-
;onday8,samples
andfor1hourafterthemorningdoseandfor1hourwereobtainedbeforedosingandat4and12hoursaf-
-ascending-dose
Bothstudieswereconductedatasingleclinicalphase,subjectswererequiredtocollectallurineforthe
center,andthestudyprotocols,subjectinformation,0-to6-,6-to12-,12-to18-,and18-to24-hourinter-
andinformedconsentformwerereviewedandap-valsafterdosing,andonday11,subjectswererequired
provedbyindependenthumanresearchethicscommit-
tees(AlfredHealthHumanResearchEthicsCommit-proceedtothenextdoselevelwasmadebytheinves-
tee,MelbourneVIC3004,Australiaforstudy1;andtigatorandthesafetymonitoringcommitteebasedon
BellberryHumanResearchEthicsCommittee,East-acceptablesafetyandtolerabilityofthelowerdose.
woodSouthAustralia5063,Australiaforstudy2).,open-label,2-
Thestudieswereconductedinaccordancewiththetreatment,2-period,multiple-dosestudytodetermine
DeclarationofHelsinkionbiomedicalresearchin-thesafety,tolerability,pharmacokinetics,andpharma-
volvinghumansubjectsandInternationalConferencecodynamicsofanimmediate-release(IR)tabletanda
onHarmonizationGoodClinicalPracticeguidelines,liquidsolutionofPN--
andallstudyprocedureswereconductedbyscientif-isonofasoliddoseformulationtotheliquidformu-
-lationthathadbeeninvestigatedintheirst-i
Single‐ and Multiple‐Dose Pharmacokinetics and Pharmacodynamics of PN‐943, a Gastrointestinal‐Restricted Oral Peptide Antagonist of α4β7, in Healthy V 2021 Nishit B. Modi 来自淘豆网www.taodocs.com转载请标明出处.