Pharmacokinetics,Tolerability, and Safetyofintranasaladministrationofreformulatedoxycontin

ClinDrugInvestig(2013)33:441–449DOI10.1007/s40261-013-0085-x

Pharmacokinetics,Tolerability, and SafetyofIntranasalAdministrationofReformulatedOxyContin®TabletsComparedwithOriginalOxyContin®TabletsinHealthyAdults

PeterJ.Perrino• SalvatoreV.Colucci•

GlenApseloff• StephenC.Harris

Publishedonline:16May2013

©TheAuthor(s)2013.ThisarticleispublishedwithopenaccessatSpringerlink.com

Abstract

BackgroundandObjectiveReformulatedOxyContin®(oxycodone-HClcontrolledrelease)tablets(ORF)became

availableintheUnitedStatesinAugust2010.TheoriginalformulationofOxyContin®(oxycodone-HClcontrolledrelease)tablets(OC)usedadeliverysystemthatdidnot

provideinherentresistanceto crushing anddissolving. Theobjectiveofthisstudywastocomparethepharmacokinetics,tolerability,andsafetyoffinely crushedORFtablets,coar-selycrushed ORFtablets, andfinelycrushedOCtablets.

MethodsThisrandomized,single-blind,single-dose,single-center,six-sequence,triple-treatment,triple-periodcrossoverstudyenrolledeligiblehealthyadults(aged18–55yearsinclusive).Thestudyevaluatedthepharma-cokinetics,tolerability,andsafetyofintranasallyadmin-isteredORF,bothfinelycrushedandcoarselycrushed,aswellasfinelycrushedOCtablets.Plasmaoxycodoneconcentrationswerequantifiedandanalyzedtodeterminethemaximumobservedplasmaconcentration(Cmax),timetomaximumplasmaconcentration(tmax),areaundertheplasmaconcentration–timecurvefromhour0tothelastmeasurableplasma concentration(AUClast),andareaundertheplasmaconcentration–timecurveextrapolatedtoinfinity(AUC?).Theabusequotient(AQ),calculatedasCmax/tmax, servedasanindexofthe average rateof increaseindrugconcentrationfromdosingtotmax.Intranasaltol-erabilityratingscales(discomfort,itching,burning,pain,

P.J.Perrino()·S.V.Colucci·S.C.HarrisPurduePharmaL.P.OneStamfordForum,Stamford,

CT06901,USA

e-mail:

G.Apseloff

DepartmentofPharmacology,OhioStateUniversity,Columbus,OH,USA

runnynose,andstuffiness)andintranasalendoscopywereconducted.Safetyassessmentsincludedadverseevents,vitalsigns,pulseoximetry(SpO2),andelectrocardiograms.ResultsOf83subjectsscreenedandenrolled,30wererandomizedtoperiod1,with1subjectsubsequentlydis-continuingduetothesubject’schoice.MeanCmaxvaluesforfinelycrushedORF(17.1ng/mL)andcoarselycrushedORF(15.5ng/mL)werelowerthanthatforfinelycrushedOC(22.2ng/mL).MediantmaxforfinelycrushedOC(1.0h)wasshorterthanthatforeitherfinelycrushedORF(2.0h)orcoarselycrushedORF(3.0h).MeanAQvalueswereapproximately66and80%lower,respectively,forfinelycrushedORFandcoarselycrushedORFthanthatforfinelycrushedOC.FinelycrushedORF,coarselycrushedORF,andfinelycrushedOCdemonstratedsimilartotaloxycodoneexposures(AUC?).InsufflationofORFproducedgreaternasaldiscomfortandstuffinessthanfinelycrushedOC,althoughthelatterproducedhigherrunnynosescores.Nosignificantdifferencewasfoundinothernasaltolerabilitymeasures.Theoverallsafetyprofilewasasexpectedfol-lowingopioid administrationinhealthy subjects.

ConclusionsIncontrasttoOC,bothfinelyandcoarselycrushedORFretainedsomecontrolofoxycodonerelease.ReducedCmaxandincreasedtmaxforORFresultedinlowerAQscoresforORFcomparedwithOC.ORFwasassoci-atedwithgreaterintranasalirritationthanOC.ThesedatasuggestthatORFhasalowerintranasalabusepotentialthanOC.

1Introduction

Opioidanalgesicutilizationforpainmanagementhasincreasedsignificantlysince1998;unfortunately,alongwith the increase in the legitimate use of opioid

medications,therehasalsobeenanescalationintheabuseofprescriptionopioids,particularlyabuseofcontrolled-releaseformulationsthatcontainhigheropioidcontent[1,2].Comparedwithsubstancessuchascocaineandheroin,prescriptionopioidsarerelativelyeasiertoobtainandareperceivedasmoresociallyacceptabletoabuse.Theyhavealsobeenmentionedaspossible‘‘gateway’’drugstootherillegalsubstances[3–5].

Experiencedabusersandrecreationaluserscommonlyemployalternateroutesofadministration(e.g.,injectingandsnorting)inabusingoralopioidmedications[4,6,7].Datasuggestthatthe incidenceofinjectingoraloxycodoneproductsamongtheseexperiencedandrecreationalabusersrangesfrom22to59%,andtheincidenceofintranasaladministrationrangesfrom45to92%[6,7].Abuseviathese routes first requires tampering to accelerate thereleaseoftheactiveopioid,whichrapidlyprovidesahighbloodconcentrationcomparedwithoraldelivery[8].Toreduce abuse and misuse, particularly by injecting andsnortingoralopioidanalgesics,pharmaceuticalmanufac-turershavebeguntodeveloptamper-deterrentproducts[2].

ReformulatedOxyContin® (oxycodone-HClcontrolled

release;ORF)wasdevelopedwiththespecificintentofreducingabuseandmisuseoftheoriginalformulationofOxyContin®(OC)withoutaffectinglegitimateuseforthe

managementofpain.ORFtabletsbecameavailableintheUnitedStatesinAugust2010atthesametimethatship-mentsofOCwerediscontinued.OCusedadeliverysystemthatdidnotprovideinherentresistancetobreaking,crushing,anddissolving.ORFwasdesignedtobeorallybioequivalenttoOC,butwithabuse-deterrentpropertiesthatmakeabusevianonoralroutesofdeliverymoredif-ficult.Duringformulationdevelopment,laboratory-basedtampertestingindicatedthat,whencrushed,ORFtabletsfractionateintolargepiecesthatdiscourageintranasalabuse,andwhendissolvedinsmallamountsofaqueoussolution,the particlesform aviscoussolutionthatdis-couragesintravenousabuse[9].

Thisstudyfocusesonintranasaladministrationofoxy-codone,becauseitis associatedwithfasterabsorptionthanoraladministrationandmaythereforepose agreater risktotheabuser[10].Additionally,intranasaladministrationinvolvescrushingorpulverizingthetablets,whichmaycompromisetheircontrolled-releaseproperties.Itwashypothesizedthatuponintranasaladministration,thetam-per-deterrentpropertiesofORFrelativetoOCwouldtranslateintoareductioninmaximumobservedplasmaconcentration(Cmax),anincreaseintimetomaximumplasmaconcentration(tmax),andacorrespondingdecreaseintheabusequotient(AQ)[6,11,12],suggestiveofadecreaseinabusepotential.

Theobjectiveofthisstudywastocomparethephar-macokinetics, tolerability, and safety of finely crushed

ORFtablets,coarselycrushedORFtablets,andfinelycrushedOCtablets,eachintranasallyadministeredassin-gle10-mgdoses.

2Methods

2.1StudyDesign

Thiswasarandomized,single-blind,single-dose,single-center,six-sequence,triple-treatment,triple-periodcross-overstudydesignedtoevaluatethepharmacokinetics,tolerability,andsafetyofintranasallyadministeredORF,both finelycrushed(10mg)andcoarsely crushed (10mg),aswellasfinelycrushedOC(10mg).CoarselycrushedOCwasnottestedbecausesimplecrushingofOCreadilyproducesafinepowder.Tominimizevariability,tamperedtabletswerepreparedusingstandardizedequipmentandtechniques.

Studydurationwasupto42days;a28-dayscreeningphasewasfollowedbya7-daytreatmentphase,withfol-low-up3–7daysafterthelastdoseofstudydrug.The treatmentphasewasdividedintothreeperiods(days1–3,3–5,and5–7).Theassignmentofsubjectstotreatmentsequencewassingle-blinded. Effortsweremadetopreventsubjectsfrommakingside-by-sidecomparisonsofstudydrugs,whichwere similar,but not identical, in appearance.ThisstudyprotocolanditsinformedconsentformwassubmittedtotheWesternInstitutionalReviewBoard(IRB)forreviewandapproval.ItwasconductedinaccordancewithregulatoryguidelinesandtheapplicableInternationalConferenceonHarmonizationguidelinesofGoodClinicalPractice,asconsistentwiththeDeclarationofHelsinki.Allsubjectsprovidedoralandwrittenconsentbeforeconductofanyprotocol-relatedprocedures.Subjectswereinformed

thattheycoulddiscontinuethestudyatanytime.

2.2Subjects

Subjectswerehealthymenandwomen(aged18–55yearsinclusive)withnoclinicallysignificantmedicalhistoryoranyotherconcernsthatwould havejeopardizedthestudy’ssafetyorvalidity,asdeterminedbytheprincipalinvesti-gator.Specialpreferenceforstudyenrollmentwasgiventorecreationaldruguserswhohadexperiencewithopioiduseonatleastfiveoccasions,andtosubjectswhoreportedatleastthreeoccasionsofintranasalopioiduseforthepur-poseofabuse/misusewithinthepastyear.Subjectswereexcludediftheyhadsignificantobstructionofeithernaris,orclinicallyimportantchangesintheintranasalcavitythatwouldinterferewiththestudyproceduresordataintegrityorcompromisedthesafetyofthesubject.Subjectswithpiercingsthroughthenoseoraperforatednasalseptum

weregivenalowerprioritythanthosewithoutthesefindings.

Otherconditionswarrantingexclusionfromparticipationwereuseofanymedication/herbalproduct[exceptparacet-amol(acetaminophen)(2g/day),vitaminormineralsup-plements,birthcontrol,andhormonereplacement]within7daysofstudydrugadministrationorforthestudyduration.

2.3Treatment

Aphysicalexamination,biochemistrytests,andurinalysiswereconductedforeachsubjectatscreening.Subjectsabstainedfromconsumingalcoholicbeveragesfor48hpriortoinitialstudydrugadministration(day1)andforthedurationofthestudy(i.e.,throughtotheendofstudyprocedures).Theywereconfinedtoanonsmokingstudyfacilitythedaypriortoadministrationofthestudydrugandthroughoutallthreeperiods ofthe study.Subjectsabstainedfromcaffeineorxanthineentirelyduringcon-finement.Whileconfinedatthestudysite,theyreceivedmealsatscheduledtimesthatdidnotconflictwithotherstudy-relatedactivities.Thesamestandard meal timingwasemployedovercorrespondingstudydaysineachperiod,butthecontentofmealsvaried.

Subjectswererandomizedtoatreatmentsequenceonthemorningofday1andreceivedtreatmentsondays1,3,and5ofthetreatmentphase,withaminimumwashoutperiodof48hbetweendoseadministrations.Foreachtreatmentperiod,subjectscompleteda10-hovernightfastbeforesittinginanuprightpositionandintranasallyin-sufflatingadoseoffinelycrushedORF(10mg),coarselycrushedORF(10mg),orfinelycrushedOC(10mg)throughashortthinstraw.Dosingwascarefullyobservedbythesitestaff,andtheweightofanydrugnotsuccess-fullyinsufflatedduringthe5-minadministrationperiodwasrecorded,withsignificantamountsofnonadministereddrugpotentiallyresultinginsubjectdiscontinuationfromthestudy.Subjectscontinuedfastingfor4hsubsequenttodosingand weretoremainupright,unlessaprocedurerequired thattheybe inthesupineposition. Theyremainedconfinedtothestudysitethroughoutallthreetreatmentperiodsandabstainedfromstrenuousexerciseorphysicalexertion.Treatmentprocedureswereidenticalforallthreetreatmentperiods,withsubjectsreceivingsingleintranasaldosesofstudydruginalternatingnares(e.g.,left-right-left).Telephonefollow-upswereconducted3–7daysafterthelastdoseorfollowingearlydiscontinuation.

2.4PharmacokineticMeasures

Duringeachtreatmentperiod,bloodsamplesfordeter-miningoxycodoneplasmaconcentrationswereobtainedforeachsubjectjustpriortodosingandat0.25,0.5,0.75,

1.0,1.5,2.0,2.5,3.0,3.5,4.0,5.0,6.0,8.0,10,12,16,24,

28,32,36,and48hpostdose.Foreachsample,venousblood(4mL)was drawn via an indwelling catheter ordirectvenipunctureintotubescontainingpotassiumethy-lenediaminetetraaceticacidanticoagulant.Avalidatedliquidchromatographytandemmassspectrometricmethodquantifiedplasmaconcentrationsofoxycodone(lowerlimitofquantitationwas0.1ng/mL).

Relativebioavailabilitywasdeterminedby comparisontothereferencetreatment(filycrushedOC).Pharmacokineticmetricswerecalculated,wheneverpossible,basedontheplasmaconcentrationsofoxycodoneaccordingtothemodelindependentapproach.PharmacokineticcalculationswereperformedusingWinNonLin(PharsightCorporation,St.Louis,MO,USA;Version5.2).Noncompartmentalanalysisofplasmaoxycodoneconcentrationsgeneratedvaluesfor:maximumobservedplasmaconcentration(Cmax),timetomaximumplasma concentration (tmax), areaundertheplasmaconcentration–timecurvefromhour0tothelastmeasurableplasmaconcentration(AUClast),areaundertheplasmacon-centration–timecurveextrapolatedtoinfinity(AUC?),andhalf-life(t1/2).Thesepharmacokineticmetricspermitassessmentoftherateandextentofdrugabsorption(bio-availability).AUC?isanindexoftotaldrugexposureandCmaxisanindexofmaximumorpeakexposuretotreatment.TheAQ,calculatedasCmax/tmax,isameasureoftheaveragerateofriseinconcentrationbetweendosingandtmax[12].Becausemorerapidexposuretohigheropioidconcentrationscorrelateswithgreaterdrug-liking,higherAQscorespredictgreaterabusepotential[6,11,12].

2.5IntranasalTolerability

Pharmacodynamicmeasurementswereassessedbyevalu-atingintranasaltolerability.Subjectsratedintranasaldis-comfort,itching,burning,pain,runnynose,andstuffinesson numericscalesrangingfrom0(none)to10(worstI can imagine).Ratingsmeasuredonlythenarisusedfordrugadministration.Intranasaltolerabilityratingscaleswereevaluatedatpredoseandat0.25,0.5,0.75,1.0,1.5,2.0,

2.5,3.0,3.5,4.0,5.0,6.0,8.0,10,and12hpostdose.At

approximately5and24haftereachdosing,subjectspro-videdawrittenresponsetothequestion,‘‘Whateffects(ifany)didsnortingthisdrugcausetotheinsideofyournose?’’Additionally,aspecialistinear,nose,andthroatproceduresperformedintranasalendoscopies.Thesewereconductedatpredose,andascloseto0.5hpostdoseaspossible,butnotlaterthan2hpostdose.

2.6SafetyMeasures

Safetyassessmentsincludedreportsofadverseevents(AEs),clinicallaboratorytestresults,vitalsignsresults,

pulseoximetry(SpO2),physicalexaminations,andelec-trocardiograms(ECGs).ReportedAEswerecodedaccording tothe MedicalDictionaryfor RegulatoryActivities(version 9.1)by preferredtermandsystemorganclass.AEsreportedhereinarethosethatemerged,ree-merged,and/orworsenedinseverityduringtreatmentandwereclassifiedastreatment-emergentAEs.

2.7StatisticalAnalysis

Subjectswhowererandomized,receivedstudydrug,andhadatleastonepostdosesafetyassessmentwereincludedinsafetyanalyses;subjectswhowererandomized,receivedstudydrug,andhadatleastonevalidpharmacokineticmetricwereincludedinpharmacokineticanalyses.Forpharmacokineticdata,amixed-modelanalysisofvariancewasusedtocomparelogarithmic-transformed(basee)valuesforCmax,AUClast,andAUC?ofoxycodone,withfixedeffectsfortreatment,period,andsequence,aswellasrandomeffectsofsubjectwithinsequence.

Forpharmacokineticdata,bioequivalencewasindicatedifthe90%confidenceintervals(CIs)foroxycodoneforagivenmeasurefellentirelywithinthe80–125%range.Intranasaltolerabilityratingscalesuseddescriptivestatis-ticsforrawdataandfordifferencesfrompredoseforeachtimepointandtreatment.Themaximumresponseovertimewastabulatedandananalysisofcovariancemodelwasconductedtoassessdifferencesamongtreatmentsrelatedtomaximumresponse.Thispharmacodynamicmodelincludedacovariateforthepredoseassessment,fixedeffectsfortreatment,period,andsequence,andarandomeffectofthesubjectwithinsequence.

3Results

Of83subjectsscreenedandenrolled,30wererandomized(Fig.1).Onewasdiscontinuedinperiod1duetothesub-ject’schoice,leaving29intreatmentperiods2and3.Themean(range)ageofsubjectswas32(19–52)years.Oftherandomizedsubjects,mostweremale(66.7%)andmostwerewhite(83.3%).Mean(range)bodyweight,height,andbody mass index were 78.1 (49.9–94.0) kg, 171.5

(156.0–187.0)cm,and26.5(19.1–31.9)kg/m2,respectively.

3.1Pharmacokinetics

Afterintranasaladministration,meanCmaxwaslowerforfinelycrushedORFandcoarselycrushedORFthanthatforfinelycrushedOC(Table1;Fig.2).ThemeanCmaxmetricratiocomparingcoarselycrushedORFandfinelycrushedOCindicateda33%lowerCmaxforcoarselycrushedORF

Fig.1Studydisposition.OC-Ffinelycrushedoriginalformulationofoxycodone-HClcontrolledrelease,ORF-Ccoarselycrushedreformulatedoxycodone-HClcontrolledrelease,ORF-Ffinelycrushedreformulatedoxycodone-HClcontrolledrelease

(Table2).ThemeanCmaxmetricratiocomparingfinelycrushedORFandfinelycrushedOCindicateda22%lowerCmaxforfinelycrushedORF.Inaddition,mediantmaxvalueswerereachedmorerapidlyforfinelycrushedOCthanforeitherfinelycrushedORForcoarselycrushedORF(Table1;Fig.2).ThehighestmeanAQscorewasobservedforfinelycrushedOC(31.7ng/mLperh)com-paredwitheitherORFpreparation(Fig.3),withmeanAQscoresforfinelycrushedORFandcoarselycrushedORFapproximately66and80%lower,respectively,versusfinelycrushedOC.

Afterintranasaladministration,meanoxycodoneAUC?valueswere124,134,and128ng·h/mLforfinelycrushedORF,coarselycrushedORF,andfinelycrushedOC,respectively(Table1).MeanmetricratiosbetweenfinelycrushedORF,coarselycrushedORF,andfinelycrushedOC areillustrated inTable2.Withmeanmetricratiosfalling within the80–125%CIrangefor all treatment comparisons,theseresultsindicatedcomparabilityoftreatmentsforaveragetotaloxycodoneexposure.

Table1 Meanoxycodonepharmacokineticmetrics(fullanalysispopulation)

Parameter / ORF-F10mg(n=29) / ORF-C10mg(n=29) / OC-F10mg(n=30)
Cmax(ng/mL) / Mean(SD) / 17.1(3.65) / 15.5(5.41) / 22.2(4.87)
AUC?(ng·h/mL) / Mean(SD) / 124(29.3) / 134(45.1) / 128(29.4)
AUClast (ng·h/mL)
tmax(h) / Mean(SD)
Median(range) / 123(29.2)
2.00(0.75–3.50) / 133(45.0)
3.00(1.00–8.13) / 127(29.4)
1.00(0.25–2.50)
t1/2(h) / Mean(SD) / 4.43(0.786) / 4.45(0.796) / 4.46(0.810)

AUC? areaundertheplasmaconcentration–timecurveextrapolatedtoinfinity,AUClastareaundertheplasmaconcentration–timecurvefromhour0tothelastmeasurable plasmaconcentration, Cmaxmaximumobserved plasmaconcentration, OC-Ffinely crushedoriginalformulation ofoxycodone-HClcontrolledrelease,ORF-Ccoarselycrushedreformulatedoxycodone-HClcontrolledrelease,ORF-Ffinelycrushedreformulatedoxycodone-HClcontrolledrelease,SDstandarddeviation,t2half-life,tmax timetomaximumplasmaconcentration

18ORF-F 10mg(n=29)

16ORF-C10mg(n=29)

14OC-F10mg(n=30)

0481216202448

Timepostdose(h)

Fig.2Meanplasmaoxycodoneconcentrationsfollowingintranasaldosingovertime inthefull analysisset. OC-Ffinelycrushedoriginal formulationofoxycodone-HClcontrolledrelease,ORF-Ccoarselycrushedreformulatedoxycodone-HClcontrolledrelease,ORF-Ffinelycrushedreformulatedoxycodone-HClcontrolledrelease

3.2IntranasalTolerability

ComparedwithfinelycrushedOC,insufflationoffinelycrushedORFandcoarselycrushedORFproducedsignifi-cantlyhighermeanratingsofnasaldiscomfort(P=0.0030

and P\0.0001, respectively) and intranasal stuffiness

(P\0.0001foreach)(Fig.4).Insufflationoffinelycru-shedORFproducedasignificantlylowermeanratingfor

runnynosethanfinelycrushedOC(P=0.0363),andcoarselycrushedORFyieldedsignificantlygreaterintra-nasaldiscomfortthanfinelycrushedORF(P=0.0106).Therewerenosignificantdifferencesnotedforothermea-suresofnasaltolerability(burning,itching,orpain).

Intranasalendoscopyat0.5hafterinsufflationofeitherORFpreparationrevealedacoarse,white,gel-foam-typematerialinthenasalpassagesofsubjects,whereasnasalpassageswereclear afterinsufflationoffinelycrushedOC.Subjectcommentscorroboratedthesefindings(seerepre-sentativedatainFig.5).

3.3Safety

Nodeathsorseriousadverseeventswerereported.Ofthe93AEsreported,25werereportedin15subjectswith

finelycrushedORF,29werereportedin12subjectswithcoarselycrushedORF,and39werereportedin9subjectswithfinelycrushedOC.OnesubjectchosetodiscontinuefromthestudyduetoanAEofnauseawithfinelycrushedOC(10mg)dosing.ThemostcommonlyreportedAEswereheadache,nausea,andvomitingandmostAEswereofmildormoderateseverity.Thenumberandpercentageof distinctsubjects with AEsthatwerejudged tobe relatedtostudytreatmentareshowninTable3.AllAEsresolvedbystudyend.TheeightAEsthatweresevereandrelatedtotreatmentwerevomiting(3),nausea(3),headache(1),andpaininextremity(1);thesewerereportedbyfoursubjects.Results oflaboratorytests,vitalsignsmeasurements, SpO2evaluations,andECGrecordingsrevealednoclinicallysignificantabnormalitiesandraisednosafetyconcernsforthestudytreatments.

4Discussion

ThisstudycomparedtheeffectsoforiginalOxyContin®(OC) and reformulated OxyContin® (ORF) on the

pharmacokinetic,pharmacodynamic,andsafetyprofilesofhealthymenandwomen.ORF,withitsabuse-deterrentpropertiesofreducedcrushabilityshowedtheintendedeffectsofreducedCmax,delayedtmax,reducedAQ,andsignifintlyincreasedintranasalintolerabilitycomparedwithOC.ThesafetyprofiofORF wassimilartothatofOC.MostAEsforalltreatmentswereclassifiasmildormoderateandwerethosecommonlyassociatedwithopioiduse(e.g.,nausea,vomiting,andheadache).

Subjectsreportedgreaterintranasaldiscomfort,stuffi-ness,andintranasalobstructionwithORFthanwithOC.Decreasedsubject-reportedtolerabilityandvisualdemon-strationsofincreaseddepositionofundissolved,crushedORFsuggestthatrecreationalabusers,intentonusingintranasaladministrationofprescriptionopioids,mayfindthatORFhaslowdesirability.Thecurrentstudyexaminesacutetolerabilityofasingle-doseadministration,sothe

Table2 Treatmentcomparisonsofpharmacokineticmetrics

Parameter / ORF-CvsORF-F / ORF-FvsOC-F / ORF-CvsOC-F
Cmax(ng/mL) / MeanratioofPKmetric(90%CI) / 86.3(76.91,96.78) / 77.6(69.27,87.02) / 67.0(59.76,75.07)
AUC?(ng·h/mL) / MeanratioofPKmetric(90%CI) / 103.0(91.64,116.10) / 97.4(86.56,109.50) / 100.0(89.29,112.94)

TreatmentgroupswereORF-C10mg(n=29),ORF-F(n=29),andOC-F10mg(n=30)

AUC?areaundertheplasmaconcentration-timecurveextrapolatedtoinfinity;CIconfidenceinterval,Cmaxmaximumobservedplasmaconcentration,OC-FfinelycrushedoriginalformulationofoxycodoneHClcontrolledrelease,ORF-CcoarselycrushedreformulatedoxycodoneHClcontrolledrelease,ORF-FfinelycrushedreformulatedoxycodoneHClcontrolledrelease,PKpharmacokinetic

120

ORF-F10mg

ORF-C10mg

OC-F10mg

isnotunexpectedgivenevidenceshowingthenasalmucosaisanefficientabsorptivesurfaceforagentsdeliveredinpowderedform[19,20].Therapidrateofabsorptionthatoccurswithintranasalnonmedicaladministrationofopioidsmayincreasetheirabusepotential.Furthermore,recentfindingssuggestthatrateofinfusionofopioids,includingintravenousmorphine[21]andoxycodone[22],isanimportantdeterminantofthereinforcingeffectsoftheseagents,withrapidinfusionresultingingreatereffects.

TheultimategoalofthedevelopmentofORFwastoreplaceareadilyabusableproductwithanabuse-deterrentproductthatreducedthefrequencyandadverseconsequencesofabusewhilemaintainingaccesstotreatmentforpatientswithmoderateto severepainwhorequire a continuous,around-the-clockopioidanalgesicforanextendedperiodoftime.Althoughnoopioidproductcaneverbeabuse-proof[1,2],abuse-deterrentproductsofferthepossibilityofincre-mentalormoresubstantialreductionsinabusepotentialcomparedwithpreviouslydevelopedproductsthataremoreeasilyaltered,dependingupontheproduct/formulation,the

Fig.3 Abuse quotient box and whisker plots. The open circles

representtheindividualabusequotientvaluesforeachpatient.Cmaxmaximumobservedplasmaconcentration,OC-Ffinelycrushedoriginalformulationofoxycodone-HClcontrolledrelease,ORF-Ccoarselycrushedreformulatedoxycodone-HClcontrolledrelease,ORF-Ffinelycrushedreformulatedoxycodone-HClcontrolledrelease,SDstandarddeviation,tmaxtimetomaximumplasmaconcentration

impactofchronicintranasalabuseofORFcannotbedetermined.However,medicalcomplicationsinvolvingthenasalmucosawithchronicintranasalsubstanceabusehavebeendocumented[13–15].

ThisstudyfocusedonOxyContin®abuseviatheintra-

nasalrouteofadministration(i.e.,snorting),whichisacommonlyusedmethodofabuse[7].OCcanbeeasilycrushedtodisableitscontrolled-releaseproperties[6,8,16,17].Thepharmacokineticprofileoforallyadministered,crushedOChasbeenshowntobesimilartothatofimmediate-releaseoxycodone[18].Inaddition,intranasaladministrationofcrushedOCresultedinrapidabsorption,withmost(approximately75%)oftheadministereddosebeingabsorbed,indicatingthatintranasaladministration

aftercrushingisanefficientmeansofdefeatingthecon-trolled-releasepropertiesoforiginalOxyContin®[8].This

route,thetamperingmethod,andthepopulation[2].

Thecurrentstudy,illustratingthedifferencesinphar-macokineticprofileofintranasaladministrationofOCandORF,includeselementsthathavebeenrecommendedforassessingthepharmacokineticprofileofanabuse-deterrentproduct[3,23].PharmacokineticandsafetyanalysesareoneoffourcriticalcomponentsusedtocharacterizetheabusepotentialofORF.Theothercomponentsconsistofinvitrotamper-testingstudiesconductedduringformula-tiondevelopment[9],abuse-likingstudies[24,25],and,lastly,epidemiologicalstudies.Thereal-worldimpactofanyabuse-deterrentproductneedstobeestablishedbyavarietyofepidemiologicstudiesconductedinreal-worldsettings [1–3, 11, 12]. Those epidemiologic studies are

currentlyinprogressforreformulatedOxyContin® [26].

Recentlyreportedfindingsappeartosupportthelabora-tory-basedtamper-testingandabusepotentialstudiesforORF,includingdecreasedratesofself-reportednonoralabuseinalargenationalinterviewsurveydatabase[27];

decreasedratesofintranasalabuseinacohortofOxy-Contin®abusersinrural Kentucky[28];anddecreasedincidenceofdiversionandadecreaseinreportedstreet

valueinsurveysfromlawenforcementagencies[29,30].

ORF-F 10 mg (n=29)

ORF-C 10 mg (n=29)

OC-F 10 mg (n=30)OC-F 10 mg (n=30)

ORF-F 10 mg (n=29)

2 1.4*

0.7

0.5*

3.3*

10.7

0.6

3.7*

21.4

0.6

0.5

3.7

3.3

DiscomfortRunny

nose

Stuffiness

Discomfort

Runnynose

Stuffiness

Discomfort

Runnynose

Stuffiness

Fig.4Comparisonofmaximumresponse overtime onthe IntranasalTolerabilityRatingScale(ITRSa)intherandomizedsafetypopula-tion.aITRSwasratedonan11-pointscale,rangingfrom0(none)to10(worstIcanimagine).bLSmeansfromANCOVA.cDifferenceofmeansbetweentreatmentsfromANCOVA.d90%CIfordifferenceofmeansfromANCOVA.ePvalueforpairwisecomparisonbetweentreatmentsfrom ANCOVA. *P\0.05 between treatment groups.

ANCOVAanalysisofcovariance,CIconfidenceinterval,ITRSIntranasalTolerabilityRatingScale:ITRSwasratedonan11-pointscale,rangingfrom0(none)to10(worstIcanimagine),LSleast squares, OC-Ffinelycrushed originalformulation ofoxycodone-HClcontrolledrelease,ORF-Ccoarselycrushedreformulatedoxycodone-HClcontrolledrelease,ORF-Ffinelycrushedreformulatedoxyco-done-HClcontrolledrelease

Fig.5 Representativeintranasalendoscopyresults.OC-Ffinelycrushedoriginalformulationofoxycodone-HClcontrolledrelease,ORF-C

coarselycrushedreformulatedoxycodone-HClcontrolledrelease,ORF-Ffinelycrushedreformulatedoxycodone-HClcontrolledrelease

Table3 Subjectswithtreatment-emergent adverseeventswithatleasttwosubjectsortwoinstancesoverallintherandomizedsafetypopulation

AE,MedDRA-preferredterm / ORF-F10
(n=29)
n(%) / mg / ORF-C10
(n=29)
n(%) / mg / OC-F10
(n=30)
n(%) / mg / Overall
n=30
Mild / Moderate / Severe / Mild / Moderate / Severe / Mild / Moderate / Severe
Dizziness / 0 / 1(3.4) / 0 / 1(3.4) / 0 / 0 / 1(3.3) / 0 / 0 / 3(10.0)
Drythroat / 0 / 0 / 0 / 0 / 2(6.9) / 0 / 0 / 0 / 0 / 2(6.7)
Headache / 3(10.3) / 2(6.9) / 0 / 1(3.4) / 5(17.2) / 0 / 2(6.7) / 3(10.0) / 1(3.3) / 10(33.3)
Nausea / 5(17.2) / 3(10.3) / 1(3.4) / 6(20.7) / 1(3.4) / 0 / 2(6.7) / 3(10.0) / 2(6.7) / 10(33.3)
Pharyngolaryngealpain / 0 / 0 / 0 / 0 / 0 / 0 / 1(3.3) / 1(3.3) / 0 / 2(6.7)
Presyncope / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 2(6.7) / 0 / 2(6.7)
Vomiting / 2(6.9) / 0 / 1(3.4) / 3(10.3) / 1(3.4) / 0 / 2(6.7) / 4(13.3) / 2(6.7) / 6(20.0)

AEadverseevent,MedDRAMedicalDictionaryforRegulatoryActivities,version9.1,OC-FfinelycrushedoriginalformulationofoxycodoneHClcontrolledrelease,ORF-CcoarselycrushedreformulatedoxycodoneHClcontrolledrelease,ORF-FfinelycrushedreformulatedoxycodoneHClcontrolledrelease

Onelimitationofthepresent studyisthatstatisticalsignificancetestingusingPvalueswasnotdone.Anotherlimitationisthattheendpointswereforpharmacokineticsandsafetyonly,andstandardizedmeasuresof‘‘druglik-ing’’ werenotincorporated.Theresultsofthepresentstudycanbemoreclearlyinterpretedinlightofsubsequentresearchlookingatbothpharmacokineticsandthephar-macodynamicsofdrugliking.

InJanuary2013,theUSFoodandDrugAdministration(FDA)releaseditsguidance,Abuse-DeterrenceOpioids—EvaluationandLabeling[31].Thisguidanceproposesthatsummarystatementsandlabelclaimsregardingabusedeterrencecanbebasedonpharmacokineticdata.Thepresentstudyemployedthemajordesignelementsrec-ommendedbytheFDAinthisguidance:theuseofthemostcommonrouteofadministrationforabuse,theimpactoffoodandalcoholtakenintoconsiderationinthedesignofthestudy,themeasurementoftherateofriseofdrugconcentration,theinclusionofrelevantpharmacokineticparameters,andthedocumentingofAEs.

5Conclusions

Incontrasttotheoriginalformulation,reformulatedOxy-Contin®administeredintranasallydemonstratedalowerCmax,alongertmax,andalowerAQwhencomparedwith

theoriginalformulation.CrushedreformulatedOxyCon-tin®wasalsoassociatedwithgreaterintranasalirritationthancrushedoriginalOxyContin®,withotherwisesimilar

safetyprofiles.Overall,thesedatasuggestthatreformu-latedOxyContin®hasareducedabusepotentialcomparedtotheoriginalformulationuponintranasaladministration.

AcknowledgmentsRoleoffundingsourceThisstudywasspon-soredbyPurduePharmaL.P.(Stamford,CT,USA).Writingassistance

forthispublicationwasfundedbyPurduePharmaL.P.andwaspro-videdbyJenniferSteeber,PhD,andHudaAbdullah,PhD,formerlyofSCIScientificCommunicationsInformation(Parsippany,NJ,USA).Further writing andeditorialassistancewasprovided byHenryAndrewCaporoso,MA,afull-timeemployeeofPurduePharmaL.P.

Authors’contributionsAllauthorswereinvolvedinthedesignofthestudy;collection,analysis,andinterpretationofdata;writingthe report;andthedecisiontosubmitthemanuscriptforpublication.Allauthorsconfirmthatthisarticleisanaccuraterepresentationofthe studyresults.

Conflictofintereststatements/financialdisclosurestatement AllauthorsaffiliatedwithPurduePharmaL.P.areemployees.Dr.ApseloffwastheprimaryinvestigatorforthisstudyandprovidespaidconsultingservicesforPurduePharmaL.P.

OpenAccess Thisarticleisdistributedunderthetermsofthe CreativeCommonsAttributionNoncommercialLicensewhichper-mitsanynoncommercialuse,distribution,andreproductioninanymedium,providedtheoriginalauthor(s)andthesourcearecredited. TheexclusiverighttoanycommercialuseofthearticleiswithSpringer.

References

1.SchneiderJP,MatthewsM,JamisonRN.Abuse-deterrentandtamper-resistantopioidformulations:whatistheirroleinaddress-ingprescriptionopioidabuse?CNSDrugs.2010;24(10):805–10.

2.HamedE,MoeD.Developmentoftamperdeterrentformula-tions:stateofthepharmaceuticalindustry.CurrDrugAbuseRev.2010;3(3):139–46.

3.KatzNP,AdamsEH,ChilcoatH,etal.Challengesinthe development ofprescription opioidabuse-deterrent formulations.ClinJPain.2007;23(8):648–60.

4.OsgoodED,Eaton TA,TrudeauJJ,etal.Abriefsurveyto characterizeoxycodoneabusepatternsinadolescentsenrolledin twosubstanceabuserecoveryhighschools.AmJDrugAlcoholAbuse.2012;38(2):166–70.

5.InciardiJA,SurrattHL,KurtzSP,etal.Mechanismsofpre-scriptiondrugdiversionamongdrug-involvedclub-andstreet-basedpopulations.PainMed.2007;8(2):171–83.

6.KatzN,DartRC,BaileyE,etal.Tamperingwithprescriptionopioids:natureandextentoftheproblem,healthconsequences,andsolutions.AmJDrugAlcoholAbuse.2011;37(4):205–17.

7.YoungAM,HavensJR,LeukefeldCG.Routeofadministrationforillicitprescriptionopioids:acomparisonofruralandurbandrugusers.HarmReductJ.2010;7:24.

8.LofwallMR,MoodyDE,FangWB,etal.PharmacokineticsofintranasalcrushedOxyContinandintravenousoxycodoneinnondependentprescriptionopioidabusers.JClinPharmacol.2012;52(4):600–6.

9.ConeEJ,GiordanoJ,WeingartenB.LaboratorybasedinvitrotampertestingofreformulatedOxyContin:aniterativeandincrementalscientificapproach.PosterpresentedattheCollegeonProblemofDrugDependence’s74thAnnualMeeting.June10–14,2012;PalmSprings,CA.

10.LugoRA,KernSE.Thepharmacokineticsofoxycodone.JPainPalliatCarePharmacother.2004;18(4):17–30.

11.WebsterLR,BathB,MedveRA.Opioidformulationsindevel-opmentdesignedtocurtailabuse:whoisthetarget?ExpertOpinInvestigDrugs.2009;18(3):255–63.

12.WebsterLR.Oxycodoneextended-releaseusinggel-captech- nologytoresistalterationandabuseforthetreatmentofmod-erate-to-severepain.PainManage.2011;1(5):417–25.

13.GreeneD.TotalnecrosisoftheintranasalstructuresandsoftpalateasaresultofnasalinhalationofcrushedOxyContin.Ear NoseThroatJ.2005;84(8):512,514,516.

14.YewellJ,HaydonR,ArcherS,etal.Complicationsofintranasalprescriptionnarcoticabuse.AnnOtolRhinolLaryngol.2002;111(2):174–7.

15.JewersWM,RawalYB,AllenCM,etal.Palatalperforationassociatedwithintranasalprescriptionnarcoticabuse.OralSurgOralMedOralPatholOralRadiolEndod.2005;99(5):594–7.

16.RaffaRB, PergolizziJVJr.Opioidformulationsdesignedto resist/deterabuse.Drugs.2010;70(13):1657–75.

17.LipmanAG.WhathavewelearnedfromOxyContin?JPainPalliatCarePharmacother.2003;17(1):1–4.

18.WebsterLR,BathB,MedveRA,etal.Randomized,double-blind, placebo-controlledstudy of theabusepotential of differentformulationsoforaloxycodone.PainMed.2012;13(6):790–801.

19.UgwokeMI,AguRU,VerbekeN,etal.Nasalmucoadhesivedrugdelivery:background,applications,trendsandfutureper-spectives.AdvDrugDelivRev.2005;57(11):1640–65.

20.MatsuyamaT,MoritaT,HorikiriY,etal.Influenceoffillersin powderformulationscontainingN-acetyl-L-cysteineonnasalpeptideabsorption.JControlRelease.2007;120(1–2):88–94.

21.MarschLA,Bickel WK,BadgerGJ,etal.Effectsofinfusionrate ofintravenouslyadministeredmorphineonphysiological,psy-chomotor,andself-reportedmeasuresinhumans.JPharmacolExpTher.2001;299(3):1056–65.

22.ComerSD,AshworthJB,SullivanMA,etal.Relationshipbetweenrateofinfusionandreinforcingstrengthofoxycodonein humans.JOpioidManag.2009;5(4):203–12.

23.USDepartmentofHealthandHumanServices.GuidanceforIndustry:AssessmentofAbusePotentialofDrugs.

24.PerrinoPJ,ColucciS,HarrisS,etal.Evaluationofabusepotential of crushed and intranasally administered oxycodonetablets.AbstractpresentedattheCollegeonProblemofDrugDependence’s74thAnnualMeeting.June10–14,2012;PalmSprings,CA.

25.SellersE,PerrinoPJ,HarrisS,etal.RelativeattractivenessofreformulatedOxyContin®:comparativeassessmentoftamperingpotentialandrecreationaldruguserpreferencesforopioidfor-

mulations.AbstractpresentedattheCollegeonProblemofDrugDependence’s74thAnnualMeeting.June10–14,2012;PalmSprings,CA.

26.CoplanPM,ChilcoatHD,BaumgartnerT,etal.Designofapost-marketingstudyprogramtoassesstheeffectsofareformulatedextended-releaseoxycodonetabletonitsabuse[abstract].Phar-macoepidemiolDrugSaf.2012;21(suppl3):446(Abstract963).

27.ButlerSF,CassidyTA,ChilcoatH,etal.AbuseratesandroutesofadministrationofreformulatedOxyContin:initialfindingsfromasentinelsurveillancesampleofindividualsassessedforsubstanceabusetreatment.JPain.2012.(Publishedonlineahead ofprint).

28.DeVeaugh-GeissA,LeukefeldC,HavensJ,etal.Abuseofextended-release(ER)andimmediate-releaseoxycodonein Kentucky following introductionof reformulatedERoxycodone.Abstractpresentedat:PAINWeek2012.September5–8,2012;LasVegas,NV.

29.DavisJ,SevertsonSG,Bucher-BartelsonB,etal.Reductionin extendedrelease(ER)oxycodonediversionratesfollowingthe introductionofareformulatedERoxycodoneproduct.Abstractpresentedat:InternationalAssociationfortheStudyofPain’s14thWorldCongressonPain;August27–21,2012;Milan,Italy.

30.Bucher-BartelsonB, SevertsonS, Davis J,et al. A comparisonofthestreetpriceoforiginalandreformulatedERoxycodone.Abstractpresentedat:InternationalAssociationfortheStudyofPain’s14thWorldCongressonPain;August27–21,2012;Milan,Italy.

31.USDepartmentofHealthandHumanServices.GuidanceforIndustry:abuse-deterrentopioids—evaluationandlabeling.