Document NEk338q9zXjaJK8omMONQQ5g8

% 4% B f ace Ro l,es Corning Hazleton Inc. AR226-00460 Sponsor: 3M St. Paul, Minnesota CORNING Hazleton FINAL REPORT Study Title: Single-Dose Intravenous Pharmacokinetic Study of T-6564 in Rabbits F. Bud W. McDonald Study Completion Date: April 18,1997 Performing Laboratory: `Corning Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 Laboratory Project Identification: CHW 6329-186 Page 1 of 34 `Corning Pharmaceutical Services oz942 - `QUALITY ASSURANCE STATEMENT cw e258 This report has been reviewed by the Quality Assurance Unit of Corning Hazleton Inc., in accordance with the Food and Drug Administration (FDA) Good Laboratory Practice Regulations, 21 CFR 58. The following inspections were conducted and findings reported to the Study Director and management. Inspection Dates From To 06/27/96 06/27/96 09/03/96 09/03/96 10/15/96 10/15/96 12/03/96 12/05/96 Phase Protocol Review Sample Collection Protocol Amendment Data/Report Review Date Reported to Study Date to Director Management 06/27/96 09/03/96 10/15/96 12/05/96 06/27/96 09/03/96 10/15/96 12/05/96 [Daa /Lior Representative, Quality Assurane Unit S57 Date 2 02943 STUDY IDENTIFICATION Single-Dose Intravenous Pharmacokinetic Studyof T-6564 in Rabbits CHW 6329-186 Test Material Sponsor Sponsor's Representative Study Director Study Location Study Timetable Study Initiation Date Experimental (In-life) Start Date: In-life End Date Experimental Termination Date Study Completion Date T6564 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.0. Box 33220 St. Paul, MN 55133-3220 Roger G. Perkins, PhD, DABT 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.0. Box 33220 St. Paul, MN 55133-3220 (612) 733-3222 F. Bud W. McDonald Coming Hazleton Inc. P.0. Box 7545 Madison, WI 53707-7545 (608) 242-7901 Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, WI 53704 August 2, 1996 August 6, 1996 September 3, 1996 April 18, 1997 April 18, 1997 3 C02944 Acute Studies Steven M. Glaza Manager F. Bud W. McDonald Study Director Jeffrey B. Hicks In-life Supervisor Rose M. Bridge Administrative Supervisor `Toxicology Support Kathy Myers Manager Calvin L. Horton Supervisor KEY PERSONNEL Quality Assurance Sherry R. W. Petsel Manager CHW 6329-186 Laboratory Animal Medicine Cindy J. Cary, DVM Diplomate, ACLAM Supervisor Anatomical Pathology `Thomas E. Palmer, PhD Anatomical Pathologist Jack Serfort/ Deborah L. Pirkel Supervisors Necropsy Anne Mosher Supervisor Pathology Data 4 02945 = CONTENTS Quality Assurance Statement Study Identification Key Personnel Summary Objective Regulatory Compliance TTeesstt aSnydstCeomntrol Materials Procedures Results Discussion Signature Table 1 Individual Body Weights (g) 2 Individual Clinical Signs 3 Individual Animal Tissue Weightsand Bile Volumes Appendix A Protocol Deviations Protocol TP6350 `Amendment No. 1 to the Protocol Hw 6329-186 Rage 2 3 4 6 8 8 98 10 12 13 13 14 16 18 19 20 21 33 5 C02946 SUMMARY CHW 6325-136 `This study was done to assess the levelof systemic exposure of T-6564 when administebryead single intravenous injection to rabbits. `The study was conducted using fourmaleand four female acclimated rabbits ofthe r -------- Hra:(NZW)SPF strain for each treatment group as follows: r-------- | Grow Control/Test | Dose Level | Number ofAnimals l Material (mg/kg) Male Female | | 1 (Control) Sterile | Water 4 2 [res | a0 || 4] [5[res [ wo |4 || [| ros [5 |roe [w |o |o 4| [ mo [ [o |] a Administered at a dose volumeof 0.5 mL/kg. b Two animals/sex/dose level were sacrificed on Day 14. The remaining animals (two animals/sex/dose level) were sacrificed on Day 29. One male died approximately 20 minutes after treatment (possibly due to the volume and rateofinjection). A replacement animal was then selected and treated in the same manner. `The animals received a single intravenous injection of the control or test material at the indicated dose level into the marginal ear veinofthe right ear. The test material was mixed with Sterile `Water for Injection (sterile water) to a specific concentration for each dose level and administered at adose volumeof0.5 mL/kg ofbody weight. Oneofthe initial males treated at 300 mg/kg (Group 5) died approximately 20 minutes after treatment. This animal, discarded `without an abbreviated necropsy examination or tissue collection, was replaced with another animal and treated in the same manner. Two animals/sex/dose level were sacrificed on Day 14 and the remaining animals (two animals/sex/dose level) were sacrificed on Day 29. Clinical observations were conducted predose and at approximately 0.5, 2, and 4 hours after intravenous injection. Additional clinical observationsand twice a day mortality checks were conducted daily thereafter until the scheduled sacrifice interval (a.m. mortality check only on daysof scheduled sacrifice). Body weights were determined on Day -6 for randomization ` 02947 - - CHW 6320-186 pinutreprovsaels(,Dbaeyfo1r4eotresDt aoryc2o9n)t.roAl mbaltoeordiaslaamdpmlieni(satprpartoixoinm(aDtealyy14),maLn)d awtatshecoslclheecdteudlferdosmacsraicfihce aaGdnrmioimnuaiplst5froaruteripoldnaa)cy.esmBbelenoftoomrdeaslcaeomnwptlhroeilschowrehtraeedstaalmbsaotleocrooidlallseacamtdepmdilnefircsootlmrlatethcietoenadnwoiimntahDlstahyaetIeax(pcbpeerpfotoxirioemntoaetfsettlhmyaet4-eo,rni8ea,l r1e2p,la2c4-e,meanntda4n8i-mhaolur(sGrpoosutp-i$njmeacltei)o,n,farnodm ownhiDcahyb8l.ooAdnsaemxpcleepstiwoenrteoctohlelseectiendteartvaalpspwroaxsitmhaetely `3a:5p-p,ro6x.i5m,ataend4-1m0.L5-bhloouordsspaomsptldoesweaatstahlesod-c,ol8l-e,catneddo1n2-Dhaoyusr p1o4satndods2e2inftreorvmalesa,crheaspneicmtailvely. An sDcahyed2u9)l,edapfporrosxaicrmiaftiecleyo2n0Dtaoy4209.mLIonfadbdiltoioodn,waatstohbettaiimneeodfftrhoem secahcehducolnetdroslacarnifiimcael(aDnady 14 or aopnperGorxiomuapte4lyfe2m0almeLoonfDbalyoo1d4 wfarosmobwthaiicnhedonflryomapcparcohxiGmraotueply2-152 amnLiomaflbwliotohdthweaesxccoelplteicotend.of AalnldssaemntplfersozweenroencderntyriicfeutgoedthaendSpsoenpsaorra.teOsanmpDlaeyso1f4osre2r9u,m tahnedacneilmlaullasrwferracetiaonnesstwheerteizoebdtwaiitnhed nseocdrioupmsypeenxtaombairnbaittiaol,n bwlaesdnvoita dtohneep,oshtoewreivorerv,entiasscuaevsa,waenrdeecxoslalencgtueidn.atTehde.Awhnolaebblriveevri,abtielde,garnosds sbeontthfkriodzneenystoftrhoemSpeoancshora.nimal were collected, weighed (volume only determined for bile), and cAlfitneircableliynngorinmtarlavtehnroouusglhyoiuntjetchtesdtwuidtyhwTi-th65t6h4e eoxrctehpetistoenoriflte hwaeteornecoGnrtrooulp, allmaanliem(a3l0s0apmpge/akrge)d tahnadt odnieedGwriotuhpin52f0emmianluet(e3so00fmdgo/skeg)ademxihniibsittreadtiaons.ligIhntaldodsistiionn,weoingehtGratoutphe4i freemspaelceti(v1e00 mg/kg) termination interval (Day 14), 7 o2948 OBJECTIVE CHW 6325-186 `TTh-e65o6b4j,ecwthievne oafdtmhiinsisstteurdeydwaassatsoiansgsleesisntthreavleenveoluosfisnjyesctteiomnictoerxapbobsiutsr.e to the test material, REGULATORY COMPLIANCE TLhaibsorsattuodryywParsacctiocneduRcetgeuldaitniaocnscofrodraNnocneclwiintihcatlheLaU.bSo.raFtoooryd SatnuddiDersu,g21AdCmiFnRis5t8r,atwiiotnh'sthGeood estxacbeiplittiyonwathsatnoatnacloynsdiuscotfetdh.eAtlelstpmrioxcteudruersesfoursceodnicnentthriastsitound,yhwomeorgeenienictoym/psolliuabnicleitwyi,tahntdhe nAontimunanlecWeeslsfaarrielyAcdutplRiecgautleatainoynsp.reIvniotuhes owporikn.ionofthe Sponsor and study director, the study did TEST AND CONTROL MATERIALS Identification `The test material material was identified as T-6564 and described as a clear colorless was Sterile Water for Injection, USP (Abbott Laboratories, Lot No. liquid. The 10-382-1T; control Expiration November 1997),and was described as a clear, colorless liquid. Purity and Stability T(ihneclSupdoinngsourndaesrsutemsetscroensdpiotnisoinbsi)l.itAynafolrystiessot mfattheeritaelstpumraitteyriaanldmsitxatbuilrietsy dfeortecromnicnenattriaotnison, ahnomdogsteanbeiiltityy/osfoltuhbeilciotnyt,roalndmasttearbiiallitwy ewraescnoontsicdoenrdeudctteo dbeoradreeqquueastteefdobr ythtehepuSrppoonssoers.ofThhies psutruidtyy. Storage and Retention `The test Reserve material was stored at room temperature. samplesofthe test and control materials The were control material taken and stored was in a stored refrigerated. freezer set to mCaHinWtaifnora| tyeemapreriantaucrceoorfda2n0ceCwith10thCe.WiTshceoncsoinntrfoalcimlaittyeroifalCorrenseirnvgeHsaazmlpelteonwi(llCHbeW)retSatianneddaratd `OmpaetrearitailngwePrreocreedtuurneed(StOoPt)heanSpdotnhseonr.disAcnaryderde.maTihnientgesctonmtartoelrimaalterreisaelrvmeasyambpeluesaenddfournoutsheedrtest testing and will not be discarded after issuance of the final report. 3 92949 Safety Precautions BESTCOPY AVAILABLE cress `The test and control material handling procedures were according to CHW SOPs and policies. TEST SYSTEM Test Animal AMdiuclhtigaalnbionno Jraubnbeit2s6o,ft1h9e96Harnad:m(aNiZnWt)aiSnPeFd sattrtahine wCeHreWrefacceiilvietyd aftro33m0H1RKPi,nIsncm.,anKBaolualmeavzaorod,, Madison, Wisconsin. Housing tAhftreorugrheoceuitptt,hethsetuadnyi,mathlesawneirmealasccwleirmeatienddifvoidaruaplelryihodooufsaetd ilneassuts7pednaydse.d sDtuarinilnegssacstceleilmcaatigoens ainnd wteemrpeersaettutroem-aainndtahiunmiadtietmyp-ercaotnturroelolefd1q9uartt0er2s3.CE,navirreolnamtievnethaulmciodnittryolosff5or0t%he2an0i%m,alanrdoaom p1r2o-cheoduurrelsi.ghtI/n1c2a-sheousrwdhaerrkelviagrhitaitnigocnyscfler.omTthheesdearcokncdyictlieonwsaesxiisntteedr,rutphteeydwteorceonddouccutmienn-tliefde and considered to have had no adverse effect on the study outcome. Animal Diet TRahbebiatniDmiaeltsHwFer#e53p2r6o,viPdeMdIaFceceedsss,toInwc.atTerheadfeleidbiitsurmouatnidnealymeaansaulryzeeddabmyoutnhetomfaLnuafbaocrtautroerryfor annutarliytzieodn.alTchoemrpeonweenretsnaonkdneonwvnircoonnmteanmtianlancotnstianmitnhaenftese.d oSramwpalteersoatftlheveelwsattheartawroeupledrihoadviec.ally interfered with or affected the resultsofthe study. SelectionofTest Animals sTthuedyangirmoaulpsswbearseedidoenntaisftireadtibfyieadnibmoadlynwuemibgehtr raannddocmoirzraetsipoonndpirnoggreaamr.tagThanedrwanedroempilzaacteidoninbtoody weights were determined on arbitrarily selected from the Day extra -6. A Group S replacement male animals acclimated for the study. (Animal No. F60093) was 9 C0R2950 Hw 25-186 Study Design Animals weighing study groups: from 2,613 to 2,998 g a initiationof treawtermepelancetd into the following --e-- = -- |_Grow ControlTest | Material | Dose Level| (mgkg) | NumberofAnimals Male Female | | 1 (Control) StWearitleer. 4 || mest | a0 | 4| 4| . tess | 00 |4[a| res [|w|o 4] Ls [ mos [ woo |[4| a Administered ata dose volume of0.5 mL/kg. b T(twwoo aanniimmaallss//sseexx//ddoossee lleevveell)wweerreessaaccrriiffiicceeddoonnDDaayy1249..Theremaining animals. VOonleummaelaenddireadteaopfpirnojxeicmtaitoenl)y. 2A0 rmeipnluatceesmaefntteratnriemaatlmewnats(tphoessnisbellyecdtueedtaontdhe treated in the same manner. Justification for Species Selection Historically, the large amount of bNaecwkgZreoaulnadndinWfhoirmtaetiaolnbionno rabbit has been this species. the animal ofchoice becauseofthe PROCEDURES Dose Preparation and Administration lTehveelteisnt Gmraoteurpisal2 w0as5.diAlunteidndwiivtihdusatlerdiloesweoafteeatrco hacrheispeevcetiavsepceocniftircolcomnatceernitarlatoirontefsotrsoelaucthiodno.se `wmaastecriaallcuolratreedspfeocrtievaechteastnismolaultiboansewdasonaditmsinbiosdtyerweedigbhytionntrtahveednaoyuosfitnrjeecattimoennitn.to Tthhee mcaorngtrionlal sctaorrveediantorfotohem rtiegmhpteeraartuorveeuarntipleardimoidnoifst3er4edt.o 52Afsteecronaddsmi.niTshtreatpiroenp,araendytreestmasionluitnigontesstwesroelutions were discarded. 10 02951 IRnetarsaovennofuosr Rinojuetcteioofn iAsdamninaicscteprtaatbiloenroute to assess systemic exposure. CHW 6325-186 CIOlnbirsnaeivcreavlnaotouibsosenirsnvjoaefctAtinioonins.mwaAeldrsdeitcioonndaulctcleidnipcraeldoobsseeravnadtiaotnaspaprnodxtimwaitceaelyd0a.y5, 2, and4 hours afer `caonnidmualcstesdacdraiifliycetdheorneaDfateyrsun1t4ilorth2e9s)c.heduled sacrifice interval (sm. mormtoarlaitlyitcyhecchkeeoknslywefrore mBaotderyiawleaidgmhisniwsetrraetidoente(rDmaiyne1d),oannDdaayt t-h6 fsocrhreadnudloemdizsaactriiofnicpeuirnptoesrevsal, (bDefaoyre14esotroDracyon2t9r)o.l `aBAnlibomloaodlodSoansmaDpmalpylee-C4(o,alpwlpiertcohtxitihomenaste/xeSclheyip4tpimmoeLnno)tfwAansicmoallecNtoe.dFf6r0o0m3a3m(aGrrgoiunpal5ear vein (lft car)ofcach hBaldooadbslaomopdlseasm(palpeprcooxlilemcatteeclyfr4ommLt)hewleerfeatrheonncoDlalyect1 e(dbfefroorme atemsatrmgaitnrearelipalelaacraedvmmeeiinnnti(smlaaetltieeo)anrw))h.iocfh escxaacmcephplatenisiomnwaetlroeatthcoealsplepericonttxeeidrmvaaattlaesplwpyar4osx.tih.me,atre1el2pyl,a32c.4e5-m-,,ean6tn.5da-,n4i8am-nahdlou1(r0Gs.r5po-ouhspotu-$rinsmjapelcoets)ito,dno,fsraeonmdwohnicDhaybl8o.odAn oo1fn2t-Dhheaoyusrschp1eo4dsutaldneoddse2s2aicnfrtirefroivmcaeles(a,cDchaeysapneicmiavlelsyc.hedAunleadppfroroxsiamcraitfeic4e-omnLDbalyoo2d9.saImnpaldaedtiwttahieson4,a,lasto8t.choealnltedicmteed o4b0tamiLneodffbrloomodeawcahsaonbitmaailneind Gfrr1oo4umpoersaDc2-ha5yc,o2wn9it)rtohvltihaaentiehmxacpleopsattneidroinaooprfpvrAeonnxiiammcaaatlvealN,yoa.3p0pFrGmo0xL0io8mf5at(beGllroyoo2du0pwt4eos oaftlelmrauolloerm) ftfreramocpmteirwoanhstiucwrheeroeunntloibyltaacpienpnertdro.irfiumTgahetede.lsyeArf1ui2emrmacLneodntfcreibflluuoglaoatdriofwnra,ascstoeibpotanarisanatemedp.slaemAplllessaomfplseesruwmeraendStored vDfreaonyzuen1e4,(woSnet.rderPyasutiloc,ree)MdtNio,ntah5e5f1Se0pe6oz)ne,rsoosrnet(DtJaoammeasinD.taJioanhntseomnp,e3raMtuEr.eTo.f&-2S0,BCld1gs0.o2b-Ct3aEiu.nn0e9id,ts9rh3oi5pupgbehudsh laifye)ste2r2mainnadti2o9nwienrtehestsoaremdeamtanCnHeWraasnydt2h1se.hsiTaphmpepeldseetsoroutbmhteaaSinnpdeocdnesplorliuroliarrxtofdrDaacaytsyioa2nf2se.armepxlpeesriombetnatianled(ionn. Pathology aTasbhsbeirgeGnvreiodauttepod$enaeaccnhriomdpaoslsyetehlaxetvaemdliien(dabtasisheoodnrtoolrny tatifhsteseurgerdocoouslpeleaacsdtsmiiionngi.nsmtOernnattDiroaanyndwo1am4s,izdtaihtseicfoainrs)dtewtdewwroieatnhiomuatlasn/sex anesthetized n 0R952 CHW 6325-186 `cwaivtah,saonddiuexmspaenngtuoibnaartbeidt.alA(nviaabibnrjeevcitaiotnedingrtohsesmnaercgrionpaslyeaerxavmeiinn)a,tibloendwvaisa ntohte dpoosntee,rihoorwveveenra, twiesisguehsedwe(rveolcuolmleecotneld.y dTehteerwmhionleed lfiovrerb,ilbei)l,e,anadndimbmoetdhikaitdenleyypslfarcoedm ienacahfareneizmearlswetertoemcaoilnletcatiend,& rteemmapeirnaitnugrteowfo a-n2i0maCls+/1s0ex/Cd.oAsfetleervetliswseureesbainleesctohlelteiczteido,n,bltehde,aannidmaelxsswaenrgeudiinsacatroednedd.DaTyh2e9 in the same mannasethre animals sacrificed on Day 14. ShipmentofTissues dTohceutmiesnstuaesti(ownhooflteheliivrercsorarnedskpiodnndeiynsg)waenidghbtisleocrovlolelcutmeedso,nweDraeysse1n4t afrnodz2e9n,(aolnodnrgywiicteh) to the S55p1o0n6s)oron(JeawmeesekD.afJteorhncsololne,ct3iMonEa.nTd. s&ixSd,aBylsadfgt.e2r-i3nEl-i0f9e,t9e3r5miBnuatsihonA,vreensupeec,tiStv.elPya.ulT,hMeN, aSnpyonrseosrpoinssirbeislpiotnysifbolrethfeoratnhaelyrseitseonftitohneasnadmdpilsepsosciotliloencotfetdhien tshaimspsltesu.dynCorHaWredtoheessenortesauclctespt presented in this report. Statistical Analyses No statistical analyses were required by the protocol. TLhoecartaiwondaotfa,RraewcorDdast,a,anRdecaonrodrsi,giananldsFiignnaedl Report copyofthe final report will be retained in the archives of CHW in accordance with CHW SOP. RESULTS Body Weights eIxncdievpitdiuoanlobfoodney wGerioghutps4arfeeminalTeab(l1e001.mgA/lklga)niamnadlosngeaiGnreodupwe$igfhetmadlueri(n3g0t0hmegs/tkued)y,wsiatchritfhieced at Day 14. which exhibited weight losses of 125 g and 13 g, respectively. Clinical Observations tIhnedievxicdeupatlicolnionficatlhesiGgrnosuapre$inmaTlaebl(eAn2.imAalllNaon.imFa6l0s0a7p1p)eathraetddnioerdmaaplprtohxriomuagtheoluyt tthweensttyudmyiwniutthes postdose. dose. The death ofthis animal is believed duetothe rate and volume of the administered 2 C92953 Pathology cuwensass Individual animal tissue weights and bile volumes arein Table 3. "The animals were not examined grossly,althoughtissueswere saved (with the exceptionofthe Group 5malethat died shortly after dosing - no tissues were saved on thisanimal). DISCUSSION The levelofsystemic exposure of T-6564 was evaluated in male and female albino rabbits when `administered asasingle intravenous injection at levelsof3.0, 10.0, 100.0, and 300.0 mg/kg. All manailmea(l3s0a0p.0pemagr/ekdgc)litnhiactaldliyednowrimtahlint2hr0omuignhuotuetstohfedsotsudeywaidtmihntihsteraetxicoenpt(iboenloifevtehdedouneetoGrthoeuprate and volumeofthe dose). All surviving animals gained `weight during the study with the exception of one Grou4p female (100 mg/kg) and one: Group 5 female (300 mg/kg) that were sacrificed at Day 14. SIGNATURE FBud4). gnald SF.tuBduydDWir.ecMtcorDonald Acute Studies 9-18-97 Date i 92954 -_-- cHCHWWe63R29a-13s6 Tablet Individual Body Weights) s eeAnime al e Randomizsion e nda r Terminal Sex Number 6) On 1) O18) D2) Group 1 (Cont-Srteari)le Water (00 mpg) Male Fe0s2 263 Fo0033 212 2m 2m 2019 288 . . Fo0ss 2653 2686 Fo0ss 2591 2685 - 2833 2907 Female 60072 20 2900 2014 . F003 2m Foon 297 2881 2805 3008 . . 3207 Fo00rs 2m 2880 - sa Group? T6564(3.0 moka) Male Fo00ss 2898 F007 29 2962 2851 3012 29037 . . Foss 2716 2% Feoass 2821 250 ' - 302 ae Female F60076 283 292 am Foon? 2698 27 a . . Fo008 2699 279 F009 282 2950 - som 320 Group3 T6564 (100 mie) Male F60060 2m Fo0os1 2634 2m 2667 292 2m . . F002 2716 2912 F60063 282 279 . - 3293 20m Female F60080 am Fooost 250 297 2613 2923 2818 . . Fo0os2 269 2858 Fo0os 276 298 - sur 3.08 ~ Notrequired. + Animal scrifced on Day 14. 1 C92955 Table 1 (Continued) Individust Body Weights 5) sex Animal _Randomizaion Number y8 ial 1) Male Fo00s4 F6006s F60066. F067 Female Fo0084 Foooss Foo0ss F008? Group 4-T-6564 100.0 mpg) 2686 2607 276 2m 2040 2m 245 2150 2538 2657 262 26% 2m 205 2892 20m Male Fo06s F0069 Fo00r0 Foon Fooos3t Group 5 -T-6564 (300.0 mpg) 2m 2865 250 am 297 29% 263 2007 2989 2951 Femle Foouss 287 2m Foougs 2661 2m F600 2913 F009 2m 299 2m " Norrequired --- "Animal sacrifoincDeayd 14, a Animal ded approximately 20 minutes posdose b Replacement animalfo Animal No. F60071. CHW 6329-186 Termial 18) Dy) 2836 . 27 . - 30m - 2962 2789 . 25m . . 37 - 2289 32 27m . . . 3a - a.7 3.106 . ame . - 3260 - 30m 15 CO2956 Table2 Individual Clinica Sigas --_--"A--nimal SSeexx NNoummbber OOsbseervaationn How Duy 1 005 220 4a00 Group1 (Contr) SterileWater(00 mye) Male F60052 Appeared Normal F60053 F60054 Appeared Normal Appeared Normal F60055 Appeared Normal orvoyy vos vor Female F60072 Appesred Normal F60073 Appeared Normal F60074 Appeared Normal F6007S Appeared Normal os vv ory vos Group 2 -T-6564 0.0 mpke) Male F600S6 Appeared Normal F60057 Appeared Normal F60053 Appeared Normal F60059 Appeared Normal voy vv oss PE Female F60076 Appesred Normal F60077 Appeared Nol F60078 Appeared Normal F60079 Appeared Normal vo a vy vy Group 3 T6564 100 mghe) Male F60060 Appeared Nomal F60051 Appeared Normal F60062 Appeared Normal F60063 Appeared Normal oy os vos vv Female F60080 Appeared Normal F60081 Appeared Normal F60082 Appeared Normal F60083 Appeared Normal vy voy vv vor + Each animal appeared normal pio focontolo Animal sacrificed on Day 14. et terial dmiisrtion. 7 Condition existed. CHW 6329-186 Days 2388 suoel i1s5a3 PvE os. ov vo os. os vos vos a os PE vos or or vos ov os or ov os os vo or vr 16 COR957 1 - v "Table 2 (Continued) CHW 6325-186 Individual lini Signs SS=ec Male Femile "Animal MuNmumbbeerr OwObsaerivionn Hour Duy 1 0o5s 2200 4400 Group 4-T-6564 100.0 mpike) P6064 Appesred Normal F60065 Appeared Normal F60086 AppearedNormal F60067 Appeared Normal vos ov vos vo FS0084 F60085 AAppppeeaarreedd NNoorrmmaall F60036 Appeared Normal F60087 Appesred Normal vos vor oy PE Dus "2388 souue i5sm vo os ss rs vos or PE vos Group 5. T6564 (300.0 mye) Male F60068 Appesred Normal F60089 Appeared Nom! F60070 Appesred Normal F60093 Appeared Normal sy oy vos oy Female FS0088 Appeared Normal F60089 F60090 Appeased Nomal Appeared Normal P6009! Appeared Norm oss vy oy I 5 Each animal appeared nomaprior Anima sacrificed on Day 14. to coral or test material admiration Condition existed. os. or rs vv os. vos Pr vs " C02958 CPE mE oem ETR nm umE om POLE Plo NED owen BED wa MER ODD oEm SEPM ou we BE i OIE Poms ool EEE oR IR IE iE Pom mmo JECT sae we ne 5oFPicemPommEmeEEmoRnnmsyBHEE OEBEMEmRm 7G0 momE NmEm MoEmmoImE :g: 8 i - APPENDIX A Protocol Deviations Protocol TP6350 `Amendment No. 1 To The Protocol ch es2s-188 0 2960 Protocol Deviations CHW 6325-186 ---- Protocol Page8, 7. Experimental Design, D. ObservationofAnimals, (3) Blood Sample Collections, (b) Method of Collection/Number of Animals, Second Paragraph, Last Two Lines. "approximately 20 mLofblood will be obtained from each Group 2-5 animal sacrificed on Days 14 or 29." --ActualProcedure Only approximately 12 mL of blood was collected from one: Group 4 female (Animal No. F60085a)t the Day 14 sacrifice interval. Page 8, 7. Experimental Design, D. Observationof Animals, (3) Blood Sample Collections, (2) Frequency, Second Line. "administration to Day 1), 4-, 8, 12-, 24-,and 48-hours post". `The blood samples collected from the replacement animal (Animal No. F60093) at the 4-, 8-, and 12-hour postdose intervals were collected 3-hours/21 minutes, 6-hours/d1 minutes, and 10-hours/28 minutes. `postdose, respectively. These deviations are not considered to have had an adverse effect on the outcome of the study. 2 O2961 - Se Coiminngy aen snyv755 . Detoeer 330 EEa7tt5, CHW 6329-186 Sponsor: St Paul,mMMisosots CORNING Hatleton PROTOCOL TPe350 Study Tule: Singl-Dose lonftaTv6e5n6o4usinPhRaarbmabciotkinetic Sudy Date: August 2, 1996 Performing Laboratory: 33C0o1mKiinngsHmaaznleBtaolnenvca.rd Madison, Wisconsin. $3704 Laboratory Project Identification: CHW 6329186 2 o2952 = . CHW 6325-186 STUDY IENTIFICATION Siagle-Dose IonfrTav6e5o6o4usiPahRaarbmbsicsokineic Study CHW 63T2e96-31s806 Page CHW No. Test Material Sponsor Sponsor's Represensive Study Director Study Location PrEoxppoesceidmeSntuadlySTuinmetDaabtlee DExapfetriRmeepntoarlDTaetremination Date e186 Tess TTMoxicology Service IMMedCienctaelr,DeBpldagr.me2n2t0.2602 SPt.0.PaBulo,xM3N322$05133.3220 TMRoger G. Perkins, PAD, DABT ToMxeidcioclaolgyDeSpearrvticmeent P3.MO. CBenotxer3,3B2l2d0g. 220.2602 (St Pa2ul3M2N2$5133.3220 CF.omBiundgW.HazMlceDtoonnaIlned. MPaOd.isBono,x W7I5_4553707.7545 (608) 242.7501 3C3o0m1inKginHsamzalnetoBnouIlnecv.ard Madison, WI $3704 SAeupgtuesmtbe,r 139,916996 October 15, 1996 2 002963 - CHW6329-186 CHW 63T29e-1s86 Page 1 SSitnugdlye-Dose ntraveoous Pharmacokinetic SadinRabbits 2 aTPsouiranspgsolesesesitnhteralveevneoluosfinsjyescttieomnictexrpaobsbuirsewhenth testmaterialisadministeredas 3. TPRhreiagscuislctaeutRdoeyrgyuwilClaoltmibpoelnicsao/nnScdteuu.cntdeadrdinGuaicdceolridnaenscewwiihththetheexcfoelplioowinngtaGtooandalLyasbisooraftdoroy nteosttbmeatceroinadlucmtiedres for concentration, slbilty, homogeneity, and sabily wil [[.X)] 2C1onCdFucRt5a8s (aFNDoAmv)egulated Sudy [[11] 4400 CCFFRR 119620 E(PEPAA--TFSICFRAA)) ({115C98N1o3k0Sa(nFiNnoa.) (38O5E0CD(1)spacse MAFF) [1] Notification Nos. 313 and $70 (spaneseMOHW) uRAnelngeulcpaertsoiscoaenrdsiu.lryesIdnuipntlhiheciaostpepirnsointoyoncpoorlfetvahireousiSnpwoconorsmkop.rliaanndcesnwoidtyhdtihreecAtonri,mtahle WsetlufdyardeocAsctnot 4 A"QTsuhsaeulripatrnoytcoAecsoUsln,uirtsatniuncdeyacccoonrddoacntc,eawnidththteheimWailscreopnosritnwfialcilbietyaoudfiCtoedrnbiyngthHeaQugaeli,ty Inc. (CHW) Sundurd Operating Procedures (SOPs) and policies 5. Test Material A WTe6n5t6f4cation B. (PThoysbiecadloDceusmcernitpetdioinn the raw daa) 3 002964 E - CHW 6325-186 CHW 63e25s-1o86 C. Purity and Suabiliy Pages foGTarhcecounSdcpieonnagtsrouarntidaoesnrs,uembseotsmcoorgneedsiaptoeiniostnisyb)is.loiltuySbafiomlpipl,uerseotafydatsenaxbdtimlasitatebyrioilaatllyvyedsheeitscelraemlilmsiantxootanrbsees) t`atThekemesinenbsaeifooasr,emdinpitslatkeaesi)ownislulnlbeesssernetqu1esttheed Stpboeorirs4ehebryetxhepeSrpoinmseonr D. RStooormagteemperarre E. sRRneesdsee,rrvveesSaammppil(ess) of ach batchot of test material will be taken or this: Tmahfaeeitrneacsiotnmmpaalteteterimiopanelroarfteustrehreeoveifsi-a2fm0plpCehsa4s)1eo0wiflCtlhbaeensdtsotturhdeeynd.raettuCrnHeWd tionthefrSepeoznersosret to F. ARentyenutniuosned test al related in-Iife measttienrgi,a wil be reumed to th Sponsor fer completion of G. ASasferteyquiPrreedcabuytiConHsW SOPs snd polices 6. Control Material A SWteenitliecWaattioenfo Injection (eile water) B. CPlheyasriccaolloDrelsescsrilpitgiuoidn C.. TtPhuhereiptpuuyrrpiaotnsydesaSnotdfabstiuhlaiibsitlysiutdyyo.f this USP grade material is considered adequate for D. RSetforriaggeerated % 002965 - CHW 6325-186 CHW 63T2r5e-I1s806 Pages E RsRetesusdeyer.rvveesSaammpplelse)sofeach batelvlotofcontrolmaterialwill be takenfor this Ttohemcaoantaronlmtateerimalrpeseerovrefs-aa2m0tplCeus)1r0wielCl.besored at CHWinafreezeset F. dARienstyceanrrtdeiemodanianfitnergiscsounarnocleomfatetrihaelimnaayrebpeoruts.edforother sing and will not be G. ASasferteyquPirreedcabuytiConHsWSOPsand policies 7. Experimental Design A. Avimals RSapbebciites @ HSata(iNnZSoWu)rScPeEHRP, Inc. @ AAgedat Initiation 2We5i1g0h3t5kat Initiation (9) 2N0ummbaleers aanndd 2S0exfemales IInddeinvtiidfuiaclatniounmbered ear tag ) Husbandry @ IHnoduisviidnugally, in suspended screen-botiom stainless stl cages 3 002966 . CHW 6329-186. CHW 63E25s-1086 Pages FAFeeodmosed,aIsnucr)e.daTmhoeufntooofdLsarboourtaitnoerlyyRaanbabliytzDeidbetyHtFhe#ma5n3u2f6a(cPtMurIer for nuritional compoacats aad caviroomental contaminants. A`Wadanatllieybrzietdumforfrwoamlaadiasustoolmvaetdiscolsiydss,tesmp.eciSfaimepdlmeiscorfobtihoelowgaitcaelr are `ccholnotreinnt,atseedlehcytderdocealrebmoennsts., heavy meals, organophosphatcs, and (@ `TChoenrteaameinnaontksnowncontaminantsinth would interfere with thi study. food of wate that EEnnvviirroonnmmenetnatl controlsfto he animal room wilbese fo m5a0i%ntai2n0%a,teamnpderaat1u2r-ehooufr 1li9ghttC1o2-2h3ouCr,adarrkelcaytcilvee. huTmhideitdyakof cycle may be intemupteddueto in-life procedures, AAtclcelaismtat7iodnays (8) BSealseecdtioonnohfeaTlethstanAdnibmoadlysweigh according to CHW SOPs. An aindeoqbuvaitoeusnluympboeorrohfaelxttraisapnliamcaeldsownilltebste. puTrhcehaasneidmaslos twhiatllnboeapnliamcaeld ipnrtoogrstaumdywigtrhoiunpnsiunseidnagyasosfusatiufdeyd nbiotdiyowne.ight randomization ) JHiussttoirfiiccaaltliyo,ntfhoerNSepweciZeesalSaenldecWthiionte albino rabit hs been the animal ohfischsopieccieeb.ecause of the large amount of background information on % 029671 : -- am oimse 0bpo as mie Page? lom:o re ety | To 32 | 00|.T, T CToro[r nom |e ooo ur|oT en T]] [eEm mTrEreoEnreToome eTro] SR i S EE rb p miteig A EBeE"Y tress (Dosing Duration B t E RBGEd E Ii E sE pm e te S e . tpr teeto,e A - COR968 - cawens1ts D. Observation of Aisls aw eTsstos es (1) Be2bCl0rei,n1iecc0a4tl 4tOfb0osrhecrocvluoairutcrpionsmsioeg,a1sl2a8Sr(ewDieysleyynf,(ci:hnepstppdim)eicay05, TCrohraenmliliaymrustnys olynhteai cesthronyee Deposas1ds4os1.de3O5olooooemo cyhoec.eooy ae @ FiGohoahhyn1wtndedierresmi,icb(eehfteosr tlsseoi(rdocpocnt1o5lsormBio1 yl29ctione(Days1), Blood Sample Catections @ scPFdirrnaeienecg,nieiooonnD(a0tysDieey11f12o34m,:urpd01f3ohur3e4dexaeyedcos5r0ee0s8tncpiol ine ov 141 Day 9) ) MBgeltodholsdaomcfpilCevsli(nlpCrcoiixeiomniue)tyolfoufmAmlwnbwieiilrsbeocoyld romrehe e2,tsrciaocynshbecosdlpaoscctisinnCt,prpowedunioDnunysy8f.eOai nyoosl 1o4e.sinn lhccdiftoomihesmionaDucyu25v.ee Ge eu) fe sil icForbnoimeitohnceopionpsstoromiveenxppchaevsha,imstapcprleoys3i0mdsly62o0nmmlLofofbaHsotodwil Se2S5opc(rootbsmicmsafyoi5m emscLlhuomcfsasrpoeldstswliielmeewtsimhesatroinddtoF8yosDoceh4 Co TS im ten on Day on 3. a 02969 - cwes186 aw eTsatss cThoensiplgled nwdilhbeessrpsastcoummtsedmpwersi SatiemoTrds SionscfTsoosercsceotlye ace tiionnsctpodmetoeoaognhPpowye1o 4t t oohnireettrweDaacrkyea1no4eniwinionlnnb.desTedhotpmeorivoinoinov,fdndseToyeetspmotcpneoSspeSoh gin The sev 1nd celts rnin sample will be shied BMJiiEmgsT2D3ao6sb0s9on SP5t0vAvve5n1e06 JpimmesnDt. oofhhenpolbeis alle wil be nied reacing he E Termination ) CoUonyncdhseoitnnlsiedlySnoagcreidfiucedgs ahned sD1eysetotsoadpoin emmosrn irSocumionnnadioincnoonneddimo4n)rwsilootar srvns,eihbadbevserhheeonvddoonAopeoonnal (i CCololcanciognin.ilmbTaersiioonlsisccoohmisiymweinnisnisTgEr)ia t g dsty or cas @ iS(OcDShsaeeyiomd14h,Sehpcerreipvoenrsnwymr(eoin plsieoomnseiognhee)trowixhghbedeoienovyeneld Ciaimhjavecrts Ceivn ,tlenvead wgcialonbeiasnrevee.ii),Tnbhevrvieinssionvdnonpcorob nga on Day 5. An hed po pero ceirenion 02970 - . CHW6329-186 CHW 63T2r9e-31s806 i`Snamnploe Cboelldeoctnisonb)owiwllebre coalsleucste(da.sdescribedinsection Page 10 07.53) ) TbghSiaelac)mh,pahalnnoeidlmCieaomillmvlweeeidcrlit,laiotbbnielec,olalnedctbedo,twekiigdhneeyds((vcoollluemcetoednl1yocneeesramimnpnlee)fforo b\eemdpiesrcaatrudreedo. f -20elCyp1l0acCe.diAnfteorsafrmepelzeerscotllteoctriosni, nthaeiaannimals will icntohnSeemeeScsgptpaoiomnonpsndloi7erns.gw0(i.iwt0hev)iie6ng,hotbnsieleow,reavenodkluifmdeeasreywcislo)lblelwsiclihloibnp,espeeTnhdtetfsotraohzmeepnpleeorsnsnodngyh[ieyes1d0 dispositionof the s)am.plTehs.eSponsoris responsibleforthe reendon wo F. NStoatsitsattiicsatlicAalnaalnyaslyesses are required 5 ARepfionralt report including those temslistedbelow wil be submited, DDeessccrriippttiioonnoofftthhee Procedures tteesstt saynsdtecomntrol materials DDeastcersipotfeixopnoerfiamneynttaolxincietffieoctns and termination `{IGnrrdeoissvssidppuaabltohlaonoliogmgyaylrfeiipnsodsriutnegiswe(aifpgphaltpipsclaiabcnladeblbaein)led vroelquuemsetsedby he sudy director) 0 02971 - CHW 329.186 CHW 63T2P9e-31S306 Page 11 9: tOhLroeicgsaittuaidloydndaouftrRi,naogriwcosDpapirteossg,rRheesessarenrovdebieSlfaotbrneepaalcv(ca)ei,pbtRlaeneccsoetrdCosftH,hWaentdionFaiflnrlaelipotRretp.osrWutihnege fodfaroul,+pirenecrhpiuooddriioatsgfoctohumoepsyleeetateredm,fsoclolinostwtreiodnlbgemsalitgoeurwiiowaglirlolsfebtcehvreeesitaaaimlnpreldeeipsoo)r,tth.aelOarnacenhgyiiveoeasrlaofpeaCpseRrW. siSmgaptnoenirsnioagrlasonftrdehaei1niredaelimrnfetpheoeerwC,iHallWlbAorefccthhhieavragefesodfr.oemTreahnaetiaSodndeitdpmioantaemlorpaieayrlineowldicoltsfltboteioasmeevnsetrothd1et.he `thCeHmWatweirlilacl,haargdeisaposstaolrafgoeefwei.lIlbfe chehaSrpgeodn.sor choosestohave CHW dispose of PDroosteocporlepaanrdatpironotroeccloradmsendments nBiofdyrweecoirgdhss ODbosseervaadtmiionnisstaion `SShaimpppliengcorlelceocrtdison records PSattuhdoylcoogryreRsepcoonrddesnce Final teport (original signed copy) a"rTchehifvoeldlowwiitnhgtshuepsporrdtyindgarae.cords will be reine at CHW but will not be WAantiemralanraelycsiipsuareccloirmdastion records ARTesnftirnmiuagmeleranrttooorcmaalnitdbermafptreieroeanztaeunrtdeeammpnaedirnhaiuteumnrisedaicrteeycrorerecdcosorrddss 3 92972 . BESTCOPY AVAii ABLE os PROTOCOL APPROVAL caw sFezusgseaas12 Ludidbas fSRpoiognesrorG's R(ePerpkirnsa, aPAnDi,eDABT Bed UJ.Pion 2 ASct8ty SDiWu.tdeMaccrDonald Comin Hazen oe. TenLrmhemeane patil CQuoalnitgy Hain Assurance Unit (6329-186)HD $540 Date 2 SEoie Pre-3-9C 2 02973 . 1 fen CHW 6529-136 CORNING Harlcion AMENDMENNOT. 1TOTHE PROTOCOL. PROTOCOL TRE3SO SingleDose InuaTvesnoeetsiPnraRrabmbaicsokinei Syof t CHV E186 i Sponsor Testing Fac :i TTMoxicology Service Medical Deparment 3C3o0m1inKginHsmaadneBnolnocv.ard Madison, WI 53704 . P5MOCBeonxer15B2l2d0g. 20.26.02 SuPaul MN 551333220 Sponsor's Representative Study Director ! RogerG. Perkins PAD F.Bud W. McDonald : Tahimsendmenmtodifhieeasllowing prionof bepress i EftciveAguse 6,199 1 iPeagper,ao7c.oExperimental DesaC,. Dosing Procedure. Add he following scion to < t (9) AaDnitiemdmaaln.NTo.eDuFRi0ep0sl7scch(eeamaGernnritd$loAmnaiuilmhepa)olsdisendSspoproeimvatiel5ey10wdsenyecrmoipsnyecseaamiinration i:7 fbiolorotmoida2sso3amcp1o0ll3e5l.cikPor.no.cfeoAsmtrhtehaeamelxpilsseealeaicctcmoprsdlinagandocoeebmpioensnpieradetldos(sm(eOyafow1e)ioDgahnyin.g :: snaimaplleasn.imTarleanttdhrlepllacaemseunbtsaenqiumeanlts00Dyayp1roicn ehessswuseaneewse uisndefor protocol. i i ; " - 0974 -r Re ET wa - cHw ens. Amedeo. 1 cwesPndg eRceemeuarnafbsoveeocmhkannpgeeeTdowi3i0e0s0herpgroocyesw ci nith he ets nd PROTOCOLAMENDMENTAPPROVAL SRraioRrelOprPaeaccdknsaiivne. Bu sgl fi FuSBywmDMici eerre e ) CNomoingoHkon, QRfteupynAdgrAee2si Ein on @s136AminD) aBrue s19% Buteoasre * 02975