Pharmacokinetics June 2006

Key Points• ThepharmacokineticsofEXCEDE® (ceftiofur crystalline free acid) SterileSuspension, whetheradministeredatthebaseoftheear(BOE)inadultdairycattleorinthemiddle one-thirdoftheposteriorearinbeefcattle,aretherapeuticallyequivalent.1,2Baseoftheear istheapprovedsiteforinjectionofEXCEDEinlactatingdairycows.

• Susceptibilityoftargetedrespiratorypathogenstoceftiofurin vitro continues to be exceptional.

• Proveneffectivenessforbovinerespiratorydisease(BRD)organismsshowsasingledose ofEXCEDEprovidesextendedtherapyincattle,nowavailableforlactatingdairycattle.

• MilkdoesnotneedtobediscardedfromcowstreatedwithEXCEDEfollowingappropriate administration.

EXCEDE® Sterile Suspension: Pharmacology, microbial susceptibility, and efficacy in lactating dairy cows

IntroductionEXCEDEisaready-to-useformulation thatcontainsthecrystallinefreeacidof ceftiofur,whichisabroad-spectrum cephalosporinactiveagainstGram-positive andGram-negativebacteria,includingsomeß-lactamase-producingstrains.Likeothercephalosporins,ceftiofurisbactericidal, in vitro,resultingfrominhibitionofcellwallsynthesis.ClinicalefficacyofEXCEDEfortreatmentofBRDinbeefandnon-lactating dairycattleiswellestablished.3,4Nowap-provedforlactatingdairycows,EXCEDEisasingle-administration,extended-therapyproductthatpreservestheprovenclinical efficacyofceftiofurandcontinuestosupportthetenantsofBeefQualityAssurance.

PharmacologyEXCEDEwasoriginallyapprovedforsub-cutaneous(SC)administrationinthemiddleone-thirdoftheposterioraspectoftheearinbeefandnon-lactatingdairycattle.ToobtainapprovalforuseofEXCEDEinlactatingdairycattle,PfizerevaluatedthepharmacokineticparametersafterSCadministrationatanewsite,thebaseoftheear.Statisticalanalyseswereusedtocomparethepharmacokineticvaluesformiddleone-thirdofearadministra-tionwithBOEadministration.TheapprovedsiteforinjectionofEXCEDEinlactatingdairycowsisatthebaseoftheear.

Scott A. Brown DVM, PhD, Diplomate ACVCP; W. Lawrence Bryson, PhD; John Hallberg, DVM, PhD; Merlyn Lucas, DVM, MS, DACT; John Nappier, PhD; Joseph A. Robinson, PhD

EXD06058

LactatingHolsteins(1,206to1,916lb)intheirfirsttosixthlactation,and>40daysintothecurrentlactation,wererandomlyassignedtoreceiveasingleinjectionofEXCEDE(1.5ccpercwt.).TwelvecowsreceivedtheSCinjectionatthebaseoftheear.Plasmawasharvestedfromsamplesofbloodcollectedat0,6,12,24and36hours,andthendailythroughDay10. Theconcentrationofceftiofurand desfuroylceftiofur-relatedresidueinplasmawasmeasuredusingthevalidatedhighperformanceliquidchromatographyassayfordesfuroylceftiofuracetamide(HPLC-DCA),5ametabolitethatserves asanindicatorfortotalceftiofuractivity.

Ceftiofurandrelatedmetaboliteswere wellabsorbedfollowingSCinjectionofEXCEDEatthebaseoftheearindairycattle.Maximumobservedplasmaconcentrationsof4.44±1.65µg/mLwereattainedby19hoursafteradministration(Table1).Forß-lactamantimicrobialslikeceftiofur,thetimeduringwhichplasmaconcentrationsremainabovetheMICcorrespondswithantimicrobialefficacy.Plasmaconcentrationsfollowingadmin-istrationofEXCEDEremainedabovethetherapeuticthreshold(0.2µg/mL),whichismorethan3to6timestheMIC90,fortargetedBRDpathogens (Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni) foratleast7days.

Table 1. Pharmacokinetic Parameters for EXCEDE Administered at the Base of the Ear to Lactating Dairy Cattle1

Cmax(µg/mL) 4.44±1.65tmax(h) 19.00±8.02AUC0-LOQ(µg·h/mL) 313±85.5t>0.2,nca(h) 205±35.7

t1/2(h) 43.92±9.84

OnedoseofEXCEDEprovidesextendedtherapycomparableto5dailydosesofNAXCEL® (ceftiofur sodium) Sterile Powder,asdepictedinFigures1and2.PharmacokineticanalysesdemonstratedthatasingledoseofEXCEDEadmin-isteredintheBOEoflactatingdairy,non-lactatingdairy,orbeefcattleprovidestherapeuticconcentrationsfortargetedBRDpathogens.

Figure 1. Plasma Concentrations of 5 Daily Doses of NAXCEL (0.5 mg CE/lb) or 1 Dose of EXCEDE (3.0 mg CE/lb) in the Lactating Dairy Cow

AsingledoseofEXCEDE(blue)canbeexpected tomaintaincirculating concentrationsabovethetherapeuticthreshold(0.2 µgDCA/mL)fortargetedBRDpathogenslongerthanfive,0.5mgCE/lbdaily dosesofNAXCEL(red).Curvesrepresentthebest-fitsimulatedconcentration-timecourseofDCA,basedonrespectivedata.6Desfuroylceftiofuracetamide(DCA)isametabolitethatservesasanindicatorfortotalceftiofuractivity.

Figure 2. Plasma Concentrations of 5 Daily Doses of NAXCEL (1.0 mg CE/lb) or 1 Dose of EXCEDE (3.0 mg CE/lb) in the Lactating Dairy Cow

AsingledoseofEXCEDE(blue)canbeexpectedtomaintaincirculatingcon- centrationsabovethe therapeuticthreshold(0.2 µgDCA/mL)fortargetedBRDpathogensforlongerthanfive,1.0mgCE/lbdailydosesofNAXCEL(red).Curvesrepresentthebest-fitsimu-latedconcentration-timecourseofDCA,basedonrespectivedata.6Desfuroylceftiofuracetamide(DCA)isametabolitethatservesasanindicatorfortotalceftiofuractivity.

Microbial SusceptibilityClinicalisolatesofthetargetedrespiratorypathogens (M. haemolytica, P. multocida and H. somni) haveremainedexceptionallysusceptibletoceftiofur.Asummaryofminimuminhibitoryconcentrations(MIC)ispresentedinTable2.IsolateswereobtainedintheU.S.andCanada,andtestingfollowedClinicalandLaboratoriesStandardsInstitute(CLSI,formerlyNationalCommitteeforClinicalLaboratoryStandardsorNCCLS)Guidelines.7TheCLSI-approvedbreakpointsforsusceptibleBRDpathogensareMIC≤2.0µg/mLorazonediameterof≥21mm.

Efficacy and Management ConsiderationsStatisticalanalysesofpharmacokineticsfrommiddleone-thirdofearandBOEinjec-tionsitesinbeefanddairycattle,respectively,demonstratethattheyaretherapeuticallyequivalent.1,2TheefficacyofasingledoseofEXCEDEfortreatmentofBRDinbeefand EXCEDE and NAXCEL are registered trademarks of Pharmacia and Upjohn Company,

a division of Pfizer Inc. ©2006 Pfizer Inc. All rights reserved.

Table 2. Minimum Inhibitory Concentrations (MIC) for Ceftiofur Against Clinical Isolates Supported by Clinical Data and Indications for Use

Organisms NMIC Range

(µg/mL)MIC90*(µg/mL)

Date Tested

Mannheimia haemolytica 1101320

≤0.03-0.25≤0.03-0.25

≤0.06≤0.03

1997-19981999-2004

Pasteurella multocida 1577 ≤0.03-0.25 ≤0.03 1998-2004

Histophilus somni(formerlyHaemophilus somnus) 859 ≤0.03-0.25 ≤0.03 1998-2004

* The minimum inhibitory concentration for 90% of the isolates

Figure 3. Study Design

PTI = Post-Treatment IntervalSR0829-7922-2002-003

Figure 4. 28-Day Treatment-Success Rates

a,b Different superscripts identify statistically different values (P<0.05)PTI = Post-Treatment IntervalSR0829-7922-2002-003

non-lactatingdairycattlewaspreviouslydemonstratedinmultiplestudies.1,2,3,4,8

Onemulti-locationstudyevaluatedthefeasibilityofusing3-,5-,or7-daypost-treatmentintervals(PTIs),duringwhich no additional antimicrobial treatment wasallowed,9asamanagementoption(Figure3).TheDay28treatmentsuccessratewassignificantlygreaterby12percent-agepointsinthe7-dayPTIgroupthaninthe3-dayPTIgroup(Figure4).MortalityduetoBRDwasnotanalyzedstatisticallybutwasnumericallylowerforthe7-dayPTIgroup.Averagedailygainwassimilarforalltreatmentgroups.AsingledoseofEXCEDEprovidedextendedtherapywithoutincreasingmortalityordecreasingweightgain.

Residue Depletion in MilkMilkwascollectedfromhealthyHolstein cowsintheirfirsttosixthlactation,and >40daysintothecurrentlactation.Animalsinthestudywereallproducingatleast50lb/dayforthe3to6dayspriortoreceivingEXCEDE.Noclinicalmastitiswaspresentbyvisualinspectionofthemilkandudderforthe18to21daysbeforetreatment.Allcowswerefreeofsubclini-calmastitisasdefinedbyallmilkhaving<400,000somaticcellspermLin4-quartercompositesamplestakenjustpriortothe

beginningofthestudy.Twelve(12)cowsreceivedEXCEDE(3.0mgCE/lbBW)bySCinjectionatthebaseoftheear.Produc-tionofmilkwasmonitoredfor13daysbeforeEXCEDEwasadministeredthrough7daysafterwards.Samplesofmilkwereobtainedtwicedailyforthefirst6daysand onceonDay7afteradministrationtodeter-minetheconcentrationsofceftiofurandmetabolitesusingthevalidatedHPLC-DCAassay,whichhasalimitofquantificationof50ppbandalimitofdetectionof15ppb.Noneofthesamplescontainedresiduesabovethetoleranceestablishedformilk(100ppb).Thesedatasupportnomilkdiscard.

ConclusionsAsingledoseofEXCEDEadministeredtolactatingdairycowsatthebaseoftheearprovidedtherapeuticconcentrationsofceftiofurandmetabolitesforanextendedperiodwithnomilkdiscard.Susceptibilityoftargetedrespiratorypathogens in vitro continuestobeexceptional.

Aswithalldrugs,theuseofEXCEDESterileSuspensioniscontraindicatedinanimalspreviouslyfoundtobehypersensi-tivetothedrug.Thoughsafeincattlewhenproperlygiven,inadvertentintra-arterialinjectionintheearispossibleandisfatal.EXCEDEhasapre-slaughterwithdrawaltimeof13days.

References1EXCEDESterileSuspension[PackageInsert]. NewYork,N.Y.:PfizerInc.

2FreedomofInformationSummary,NADA141-209,EXCEDESterileSuspension.NewYork,N.Y.:Phar-macia&UpjohnCo.,adivisionofPfizerInc,2006.

3HibbardB,RobbEJ,ChesterST,etal.Dosedeterminationandconfirmationofalong-actingformulationofceftiofur(ceftiofurcrystallinefreeacid)administeredsubcutaneouslyforthetreatmentofbovinerespiratorydisease.J Vet Pharmacol Ther 2002;25:175-180.

4HibbardB,RobbEJ,ChesterST,etal.Dose determinationandconfirmationforceftiofur crystalline-freeacidadministeredintheposterioraspectoftheearforcontrolandtreatmentofbovinerespiratorydisease.Vet Ther2002;3(1):22-30.

5HornishRE,HamlowPJ,BrownSA.Multilabora-torytrialfordeterminationofceftiofurresiduesinbovineandswinekidneyandmuscle,andbovinemilk. JAOAC Intl 2003;86(1):30-38.

6WinNonlinEnterpriseVersion3.2,two-compartment modelwithfirst-orderabsorptionandeliminationprocesseswithnotimelag.

7PerformanceStandardsforAntimicrobialDiskandDilutionSusceptibilityTestsforBacteriaIsolatedfromAnimals.Approved Standard. 2nd ed. Document M31A2.Wayne,P.A.:NCCLS,2002.

8MeyerJA,etal.EfficacyofEXCEDEfollowedby3-or7-daypost-treatmentintervalsvs.Baytril®fol-lowedbya3-daypost-treatmentintervalin treatmentofbovinerespiratorydisease.Technical Bulletin No. EXD04024.NewYork,N.Y.:PfizerAnimalHealth,2004.

9HibbardB,etal.Outcomesof3-,5-,or7-day post-treatmentintervalsafterasingleadministrationofEXCEDE.Technical Bulletin No. EXD04023. NewYork,N.Y.:PfizerAnimalHealth,2004.