`Printed £33 Great Britain, All rights reserved
`
`WZZudS'ifé USS‘ 53133 «3» {3788
`Capyrigh‘. (g: {989 Fergamen he“ pfie
`
`EXHIBIT D
`
`PHARMACfiKENETECS {3F "E‘HE
`
`ANTEFRGGESTERGNE RU 48%“; EN WQME‘N
`
`DURING MULTIE’LE 393E ADMINISTRATEON
`
`Stcmid Research Labemmzy. Deeenmem 0f Evieéimi Chemists; Univeseity cf fieisieki,
`Heiefinki, Finiami
`
`05mm HElxxNHEIMm
`
`{Receiaed 3E Qcmber i987; receivedjbr pubéz'cmfen 4 July 1988')
`
`SmmarymSemm Lewis 23f RU 436 were measured by higi‘i performance liquid chromatography
`(HP‘LC) feiiowing emi §n€ake 01" 32:3, 25, 5‘3 and Emmg twice daiiy (bid) fee 4 days, 5%} mg bid.
`far 2’ days” as we}: ae a singie dese of [Zimmg bf RU 486. The yhamamkinetics (31“ RE} 486 were
`{set hem: whee ihe daily (£936; :25 RD 48% was £88 mg er mere; the serum ieve§s were simiiar. The
`pharmamkinezie behavmur of RU £886 during :he tx‘eaimen: period was simiiar between the Study
`subjects; whereas the elimination phase pharmamkmetics skewed wide findividuai variation, Also
`the: mean efiminaiitm phase halfdifes (t1 ,2} at‘ RU 5156 varied from 255 m 478 h in the groups 01"
`different regimen. yet the variation between different groups was not statéeticafly significam. The
`wees under the concentration curves (AUG) were: caiculaiecé.. In the muiiipie dose study {3:65} the
`AUCMWS deeteased when {be administereé dose of R1} 486 was inefeased The AUCSdm seen
`afiez' administratien cf
`:36 mg me. x 4211. {mean : SEM n {M3 1; $194 ,5: 53161;“: x Eafmg} was:
`signifieaefiiy (F «: {U353 §<>wer (has:
`the AHCG_.m:s chained wizh admieistratéez} 0? E25 mg
`bid, x M. (L49 : 037‘ gamed/“i x h/mg), 25 mg bixi x 4d. {L09 i 6.1:? ,umoE/i >< “rt/mg). and 56 mg
`bid. x 743. (£3.72 i (Mi ymnE/‘i x Exfang). The AUCQWW obtained by adménietraaiwn [3f :3 sizxgfie deer:
`of 28% mg of RU 486. (sds) was 0.67 i ()2? ymoE/I x h/mgd it is conciuded that if multiple dose
`administmtim of RU 486 {Is preferreé, daily administratien of reiatfiveiy Sinai} doses of RU 485 Mm»
`eevewi days seem :0 be advantagwus.
`
`ENTRGQUEX'EQN
`
`En attempts to terminate early human pregnancy,
`varieus regimens of Rim amigmgestemne RU 486
`have been usmti. k: ihe smdies pubfiisbed 543 fer, the
`oves‘aii success rate with treatment pefieds of 2v»?
`days. and daiiy deses m” RU 436 ranging 5mm 59 m
`43% mg, has varied {mm 6:} to 85% {14:3}. However,
`m“: dear dose—»-respome currelalien with clinieai per~
`femaamee has been found HQ: Preliminary reports
`suggest aha: in very eafly pregnancy a bug: single
`6303:: of RU 486 {$3. 686mg} fie ciinieaily as eifective
`as multipfie deem adminiszretien QE‘ the mmpaund 1?}
`Om earlier work an fine initial pharmaxsskmetice of
`R1} 486 foilewing single era} doses ranging €er
`106
`to 800 mg revealed shat serum levels at” RU 486 were:
`generafiy mi signifieanfly different; parfly became bf
`saturmiee cf the serum biedmg eapacity {m RU £86,
`and egeflive meitabciism 0? five compensé {8}, Serum
`ieveis of giameshyiafied and hydroxyiaied meiaboiites
`of RU 4% increased along with the imreased dese
`feiluwing single oral administration of RU 486 to
`femaie vaiunteers E8}. Hence, :0 study we gnharmw
`mkineties cf RU 3336 in wemem daring maritime siege
`
`’“Adsimss fer csrrespondence: Steroid Research Labormery,
`Depanmem of Mediee} Chemistxyg Universizy of
`Helsinki, Siltavuon‘enpmger It} A. SEMI?!) Helsinki,
`Finiand.
`Presented in gar: a! the Firs; Ewapean Cmgmss q! 15‘me
`crehcéogyg {Iomsmagea}, Denmatk, 198'?
`
`21
`
`administration as“ me cempoued, semen éeveie 0f R1}
`485 foiiowing various regimens were examined.
`
`EX?EREMENTAL
`
`(E? ~hydroxy»§3§«(4afiimethyiamimo
`RE 486
`phenyi}37a,{propynynestmdfiAbdien—bone} iabiefis
`(5‘ 16 and 56 mg), EffiJ-‘HIRU 48s“: and the eerie
`mending antihady were kindiy donated by Retasseiw
`Uciaf Research Center
`(Romainviiie, France).
`Heaithy nemaby mebstmaiing female voiemeers,
`aged 2243 yr and weighieg éfi—m kgg participated in
`the Siufiy
`
`Mulzipie dose study {ends}
`
`{imam ingesting 12.5, 25, 50 and 100 mg of RU
`485 twice fiaiiy {b.id.) for 4 deg/5‘ and Si) mg bid. for
`3’ days‘ each comésted 9f six veiunteers. Thus the
`£623.? deses of RU 486.6 were me, 3%, 469, 8&3 and
`7% mg1 respectiveiyl Vniueteers were acivieed {as Em
`gas: RU 4386 at $3046.30 and at 2E.OQ«22.0€)E2.
`begiming cm flay 32 of the Euteal phase {day 0) 6f the
`cycle during an hCCnihdlefid pseudogu'egnaney {me
`details. see ref. 91. Rims}. eaeaeies were ceiieeted daiiy
`at 96:} h min; to ingeeiion of RU 485. in the greups
`ingestieg RU 486 for 4 days or "5’ days, serum sampies
`were cgiiemed daiiy by to aiay 5 or day 7, resyeetiveiy.
`figure 1 depicts the pmweoi of RU 486 adminis~
`sraiéon and sampie eollectim. Same Samples were
`also eeEEeeted at. 9X26 b daring the £2 {iays feiiowing
`{he am? e? RU 483’; admitxistraiiim.
`
`NEPTUNE GENERICS — Ex. 1013
`
`Page 1
`
`NEPTUNE GENERICS – Ex. 1013
`Page 1
`
`
`
`22
`
`{35mm HEEKXNHEIMO
`
`.55 M91.
`‘
`i
`‘6
`RU 486
`m o-~—-<r 12.5w; ma, x 4:!
`w-uv 500 "
`9....” 251.0 n
`'-
`‘1
`chm—0100.0 '~
`meanvEEfi-fi
`
`" ‘Hgn%
`...5\
`fig
`
`
`
`5
`
`25.}
`if:
`
`D.
`
`1121';
`
`me
`
`0135
`
`0025
`
`SAM-”1.5::
`
`)7 I: a{I16‘,
`
`1. The. proximal m” RU 481‘: adminisn‘azmn mg; 59%
`Fig,
`leader: of serum sampies in the: mnlzipie 11056: $111631.
`
`$111336 5312.19 .9311de {351's}
`
`The group ingesiing 23 31:13:11: aims 01‘200 mg of RU
`486 in the mid—lutaai phase 01" the cchs (fir—18 dayg
`after 11113 LIVE-surge) consismd of 4 femaie volunteexrs.
`Biood samples were collected at — [,1’2. 0. E. 2. 4. 6
`and H321; thareaftm‘ daily 111;: to 7 days 311113 on days
`10 and 14.
`Serum lfiveis 0f RU 486 was. measured using
`Chrosxmscrbg—coiumn
`chmmaiagraphy prim m
`quaznimtitm by high perfermance iiquéd shrew
`matwmphy {HE-”LC; Elm. ?ri Lhasa HPLOsmdées aha
`itfira- and 521161215321)! magi-311313125 (if 1221111316011 were 6.9
`3:25:
`i 1.5%, respemiveiy.
`En mds {he concentrations of RU 4851 measured 11m
`
`days £411 and 3—7 foilewing 4 and 7~day Ereazments,
`rcspcciivciy. are: referred to as (Tm. Th1: normalized
`arms
`1133:1131
`the
`serum concentration
`cuz‘vfis
`
`{AUQ 1:253 were calcuiazcd ever 0m: (11333.36. intervaé
`by trapezoidal rule using the Cm : 3 measured (m days
`3 emci 4. 111161 thereafter divided by (he wiresponding
`dose in scis the AWL} ,1 was caicuiated by the
`lmgzezoiéa} rate, and 1111116313611 divided by the 11051:
`It: Ends. 1.131: 11111—111115 {333} were caicuizzwd {mm the
`cazzszazmratims 01" RU 486 :masursd 56110112ng Eermé»
`2121171011 of’RU 486 admmésn‘asisu. and in ads 1103:: {ha
`mncemrazians of RU 4861 measured after 24 h.
`0:11:«-way anaéysis of variance {ANGVA} was used
`10 2383635 ihc difilexence in ABC. and a“ betwe‘cn fihc
`gmups of“ diffamm z‘sgimcn. The AUCIS obtained by
`various ragimsns were. thereafter Gamma-ed 113mg Ehe
`Welsh twwtaiied r-iest. In ands thfi dies: of time and
`
`regimen (11‘ RU 486 on Cmmzs measured ma days 1114
`were. evaktmtcd using Ewca—way ANO‘JA. T 5 AN?
`OVACS wen: perfermed with
`121:: SmEWm‘ks-----
`82211151158233 sgafthzre (Crickci Sai‘iware, Inc. Phiiadei-
`pi 1'22. FA, U.S.1~\.).
`
`RESU {HIS
`
`Figure 2 Shaw‘s I‘m: serum cmacemmtions 0f“ RU
`486 {mean + SEM) {allowing era} administration at”
`12.5. 25. 5% and E01} mg of RU 4361 bid. for 4 days.
`
`O
`325 days
`:MW"
`10
`
`Fig. 2. Serum 321111235 5)? RU 486 (rsaean+ SEEM} i‘céiuwfing
`ingeaiion as" 12.5, 25, 5!) and 1&3 mg (of RU 6386 hid. R1? 13
`$8338.
`
`in at} groups the highest mean CNN were 1711:13wa
`13:: day 3. and they were L7. 2.6, 3.6 and 3.8;1moif'!
`in the: groups receiving {2.5, 25, 50 and 108 mg of RU
`486 EMIL. rsspcctiwly. Four 131:: first 2 days if the RU
`486 trmzmem. the CW: 3; wen: at the. same Ewe! in the
`groups ingfisting 2... 56 01* EGO am; (if RU 486 hid.
`Thmughcm the shady. the Cm of RU 486 seen aftm‘
`the dose a}? {2.51 mg ?1.i.1i.we:re appmximamiy hail!" 1)?
`these; seem afifii‘ the higher (£05135 of Si} and 368 mg
`bid. {T333111 E}.
`1311‘
`and
`syméxzis‘}
`{011m
`The
`iexdivéciuai
`new + SEM (ssiid Céz‘c‘m) serum umcemiraiions of
`RU 486 fcafiowirsg 7-day administrestim of 51) mg of
`EU 11813 bid. are depicted in Fig, 3. Serum leveis
`were simiiar 10 those. men after the 4-day treatmem.
`The highest mean CW at“ RU 486 (3.3 ymoi/E) was
`measured on day 3. ”i‘he: mean (roracanta'atimm ware
`measured 1:) remain ahave 22.2 umci/‘i througbaut the
`'fiday treatment. period, and thereafter they began 10
`ficchnc. During 111,1: Ermammt games} the individmai
`szs 01’“ RU 486 war: simiEar in aii Six valumems.
`Howsver, {ha ehminatéan pheasc pharmacokztmtics
`showed 3, wiaie ragga 131‘ variaiiun. The :52 1:11" RU «$86
`in thew patimtg was 439 3: £1,211 {mean i SEEM}
`{Tabkz 2}. E12 310312111681 N0. 1, RES 486 wag datcctabic
`in 512mm 11p 10 32 day; fuiigwing Laminaiien 13? {he
`RU 436 administraticm.
`
`in the sampies coliccwd faiiowing adminéstration
`
`Tabfic E. Serum wnccmraLiuns (yum/1) MR1} 486 [mean 1 $53M (“)1 fullnwmg ingcsxfinn 412‘ [2.5 mg
`
`
`
`
`
`
`
`
`H1.cu9.5365319?(“1w"-taunt-«xv
`
`w1.14
`,mp...m.,Au.rm.1'»L):LI-0“U‘a):,1...“a1.;m,M,
`
`NEPTUNE GENERICS — Ex. 1013
`
`Page 2
`
`NEPTUNE GENERICS – Ex. 1013
`Page 2
`
`
`
`Phamacckénefics of R15 4&6
`
`23
`
`Tabie 2. AUC0_,m‘s and ths imam 3: SEM. {M} fallawing Emmy
`{inn 0? 32.5. 23, 5.0 and 163ng bid‘ for d (jaw and 50mg bid, far
`‘7 days« Aiso Avg”; and rm {aim-wing ingestion of a singia 43mg
`0? 2% mg is: inflamed.
`2m
`Mia:
`{Emma}
`(snmaéii x himg}
`Regimm
`259.5 2: 3.6 {5)
`L49 : (137 (6}
`125mg ma. )4 M
`23.5. g 1.4 {in}
`F.0‘9io‘15 (6}
`zs‘flmg bid, t»: M
`3% i 4.013%}
`(378 i (121 (5}
`53.0mg {8.5114 x m
`4788 '1 7‘8 (6)
`3.43 7: mm {6)
`swam Md. x 4d
`466.9 4; 6,2 (5}
`{3112 i am (53
`59.9 mg bid, 3: 7d
`293 -_i 8.3 (4}
`{11571- 031 {4,3
`291) mg single dense
`E322
`33$?
`ANGVA f
`6.2:}
`526
`$1“
`
`
`P < 0.625P ms
`
`"5’ clayg, the seamen»
`0f 53mg of RE} 5'86 £33.41 {a}:
`ir'éifimns {3f RU 685 were 2333:; measzired by REA
`foiiowing
`the: Chmmasmbgrcofiumn
`ahmmatm
`graphy as described cariier {103. There was a gmd
`correlation between the serum levels cf RU 43$
`measurcd by HPLC and RM (Fig. 4:». The sob
`minim“: wefiicicm was 0.92 {n- s 89}, but a: 331:. strum
`ccsneemratims
`excwd-ing $1851 gimaiii R311. gave
`héghcr waives may: HPLC. The equatim Fm 3333 iinam
`regressitm line was HPLC r: 0.55 REA + (35.29 pawl/3.
`Figure 5 depicis the mean cancemrations (+ SEEM)
`9f RU 486 in bur wmnen after fiinglc 0m} intake 0f
`Zififlmg 0!" RE} 486! The paak levels of RU 486
`(mam i SEEM :2 4.“) i; 3.2 ymcfis’i} were measured at
`Eh after ingiastian, Afiar 1335: 5mm: mdisiribmim
`perimi within 6 E2, 3 piawau was washed mm
`24 in. The mean {i SEM) goncmtrau‘on of RU 486 at
`H, 2 ami
`3 days were 158 j; 9.4, 1.1533 and
`Géiflfiymwfi, fewest-may The r”; 8f RU 48:5
`in £23838 subjects was 25% i 8.3%: {mam}: SEM3
`"Rabi: 2.).
`The 33mm concentrations of RE} 386 measurcd for
`the first 7 days in the mix are diagflayed in Tabie 1.
`in 311 groups of difiarem regimen ms highest mam:
`Cmn ware measured 3 clays 3.3%: bagizming 0%" m:
`RU 48$ treaimcm. Twewway RNQVA (aid 310$ Eadb
`cam: stafégiicafiy szigzaifiaram cfieci 0:” time cm {Twins
`measures} (in (hays
`1—4 in the: gmsxps of (imam?
`regimen (ANQVA f2 “5509 {ifm 3,513, 1’ == {“82}.
`Table 2 ShOWS the: AUC:$ and rings of RU 486 in
`ali the: grmsps {3f difi'crcm regimen mudied. {Mammy
`ANGVA reveaifid statisticai‘ay signéficam vafiaiian in
`$115 AUC:S {P <0.325} caEcuiami far 6.2m: ééfi‘armi
`gmups. In {he més the AUCWWVS dacmaseii when
`the administered dose of RU 48% was increased, tha
`smaiiest AUC3,.W was chained with the regimen of
`190 mg bid. for 4 days. The AUCaamm lbiiowing
`ingestmm cf 12.5 mg {P < 8.95}, 35‘!) mg (P <: 31305)
`bid. x 4:: and Sng hid, x 7d {P {935} were
`swiisiicafiy significantiy (iifi'asesm when campared by
`the Weigh twaotailcd E-Ecst m 133:: AUCgflm £052)“;-
`ing ingestion 33' 1% mg of RU «38% 33.12.62,. x 44.
`The mew 1,,225. skewed a wide range 9f variatimi
`between the gr ups; of difi‘flem RU 486 regimen,
`hewevesz' amnway ANG‘VA did :20: indicate statisti»
`
`3.3. 72153.4:
`
`sally signifisam variatiom batweem the in: : s maasumd
`in thc difi‘ercm gmups.
`
`WSCQSSNEN
`
`Vafiaus 0m} dams Of RU 485 have: best?) used in
`eiimicai wark‘ Large dases of 224% mg of RU 486 are
`requimd far clinical amigiucocurtiwid effectS {i i. 12};
`whereas the optima? rcgimea cf RU 436 {05' mm»
`gimgcstm'onc actiefi
`rsmains Obscure g’E-néi. 3&th
`(Eases 13? 513mg or mare 0f RU 486 have been used in
`previnus ciinisxsi stusiies m 1mm :9 scrminam early
`human pxegngiscy [1431 Wifih two difi‘ermfi regimens
`(sf RU 486,
`£313: 25 mg and 5% mg bid. for 7 days;
`Gdi'md and Birgerson reported (3:49.31 success rates; 13?
`{EVE 54}, Using more strict patient Eeiectém arm threat:
`difi‘mzm: regimens of RU #362. fiamtfiy :38 mg bszi f w
`4 days, 50 mg 3 {imeg daiiy fm' 4 fiaysg and 408 mg
`daiiy for 2 days, Couzinei £1 alt were abie £0 terminate
`eariy pregnancy equaily in 32‘ $8 and 85% 01‘ their
`patients, a‘esgacciivciy {3). Success mics of {i0 and 72%
`repertcd by Cameron et ai. magi by Shuupfit £1 :21.
`faléewéfig ingeazien Gf {5‘3 mg G33}; far 4 days 3216i
`20% mg daiiy 5m- 7 days, respcmivafiy, are is: me, seam:
`range am the other ci'micai data pablished $0 far {5, 6}.
`Recent mpam suggest that administrating 0f RU 486
`at daily dosscs of 25 and 58 mg might hr: at: {hit
`ihresheki if being cfi'eciévc {m induciim: of uterine:
`bias-fling m far iamimtien a? eafiy pregnancy, rem
`sipsciivaly {H meafiifi, pars“ mmmmz., 33
`in mammal)» pubiishcd ciinicai artécies, the serum
`leveis 03‘ RU 436 have bean measurcd by (lirmt REA
`{3, 14, 35; which aim msasures same of the matabo‘
`flies a)? RU 4845 {14} ’E‘he Eewer gmcésicm and Mew
`racy 6? RM at high mmmtmtiqm of RU 485 {£3}
`80336 expiésin the. flights names attained by ibis
`methoei (Fig. 4). Din: =10 its higher accuracy at high
`serum lav-3:33 sf RU 486* the Emcific HFLC metlmd
`was chosen for the present study
`
`za'fim
`
`=3
`
`0&3
`
`‘1
`
`$
`
`‘13
`
`1:3
`
`mm
`
`Fig. 35 The individual (open symbols) and mean +~SEM
`(closed circles) scrum conmtz'ations of RU 436 f’cllewiiig
`intake mf 53 mg MAE.
`€01“
`7 days.
`the {1:2 63" RU 435
`{mam iSEM} in them: miumcers was 40.9 i 652 h.
`
`NEPTUNE GENERICS — Ex. 1013
`
`Page 3
`
`NEPTUNE GENERICS – Ex. 1013
`Page 3
`
`
`
`24
`
`U
`i
`I
`
`1c amu—
`715
`
`s
`NC
`
`25‘
`
`h
`
`”6/
`a//
`a
`o /
`“a
`a‘ 0
`n
`a «9 Qty/y,
`:5
`s
`53"
`
`°
`
`o
`
`“gag:
`
`I
`
`
`
`REA
`
`40"351‘391
`16.0
`7.5
`5'3
`25
`o
`and RM after
`at“ RPM:
`4. Comparison
`Fig.
`Climmnsnrbgrcolmm (slimmzilogmphy in the assay {35 RU
`486 in serum. Serum samplei were onllccted fallnwing oral
`intake of 50.0 mg bid. for 7' days. The equation for Elie
`linear regression line was HPLC : 3.55 REA + (129 umoljl,
`and the corrslation coellicl-ant was 0.92 in = 86).
`
`Partitions work an the phamacokinetics of RU 5186
`has Shawn that by increasing 2i single oral close from
`it‘ll) in 390 mg, the serum lnvels of RU 486 cannoi he
`greaily elsvalsd [El A similar phenomenon has alsn
`been reported- ts occur during multiple dos-e adniinisi
`trzttinn of the. minimum [in]. This aqual CM; 5 of RU
`486 during the treatmnnt period {allowing intake of
`daily (lanes sxcaeding Si) mg (Table l) is at least partly
`explained by saturation of alpha l~acicl glycoprotnin,
`the specific transport protein 63" RU 486 l8! 17}.
`The
`sarum concentrations
`of
`the
`mono—
`
`dcmcthylatecl, didcmsthylatcd and hydroxylatcd me»
`tabolitcs of RU 486 increased significantly when the
`single oral dose nl‘ RU 486 was increased from lilCl
`to Bill) mg;
`thus equalling 0r exceeding lhe Serum
`levels at" the parent RU 486 {81 Thcse nietalmlites
`bear inwcr affinities {if Q~Ql% (RU 436 m 100%) to
`this human pmgestcmne Escapism {l8}, Even though
`the monodemethylated and liydmxylated metabolites
`behave as weal: antiprogestcmnes in rat Elli},
`the
`antipmgcstagenic nature 0f tlm nintabnlitcs of RU
`486 in humans hail not been cnnfirmed. Thus, from
`
`20‘9ch
`{CHI
`
`5%
`'1
`
`a, LA
`a 'u
`22
`I!
`
`\x
`
`203nm
`mean - SEM
`
`m ““in-------
`2
`3
`
`4
`
`5
`
`5 days
`
`Fig. 5‘ Serum concantmtinns m” RU 4% in inn: fnmale
`volunteers (mean + SEM) following oral intake of a single.
`dose of 260 mg n? RU 486.
`
`OSKARl HEEKlNli’EIlMO
`
`the pharmacoliinetic point of VlCWi the opiinia] dns~
`age could be the one landing in thc highest serum and
`target
`tissue levels of RU 486:
`the strangest com~
`petitor for the prngestemne receptnr and the best
`characterized antipmgestemnn of these stnmids.
`in agreement with previous pharmacolcinetic data
`ill). in}, 4 and 7nclay tmaimcnt with daily doses 01“ 100
`and 200mg 0f RU 486 resulted in nearly identical
`szs of RU 486 (luring the treatment period
`(Figs 2 and 3. Table l). In the mils the AUCGWQEZS
`decreased whnn the administered dose of RU 486 was
`increased (Table 2'} The AUCQNW seen after admin—
`istration of Elli) mg bid. for 4 dayg was significantly
`
`lower than the All'{?¢_:;1..:s nhtaincd with adminis-
`tration of E25 mg hid.
`(P <10.05). 25 mg bid.
`{P <20.0tl§) for 4 days. and 50 mg bid. {P <0.05)
`fnr 7 days. This may further suggest that if multipl:
`class administratian ol RU 486 is pi'afcrred, daily
`administration in"
`relatively small
`(in.
`around
`50406 mg/(lay) singli: doses nl‘ RU 4236 might be
`advantageous. This might also decrease possible side—
`efl‘ccls 0f RU 486 associated with high oral doses
`{6, l5],
`The Elimination phase phannanolcinciics 0f RU
`486 showed a wiclt: range of intlividiial variarinn
`(Fig, 3), suggesting large individual variation in the
`capacity to metabolize and excrete RU 486. The
`mean {“335 of RU 486 varied from 25.5 to 47.8 h in
`the groups at" iiillcrnnt rcgimnns (Table 2). however
`the variatlcn was mat statistically significant.
`A large single doses nl‘ RU 486 (in.
`(308 mg) has
`been imported to be clinically equally effective as
`multiple (loge administration in very early pregnancy
`{7l The AUCQVW, following intake (if E’: single dose of
`2.00 mg of RU 486 was in the 3am: range with the
`Al_l(30.,m,:s 53m in mds (Table 2')
`indicating that
`single (inst: aeiininistrzninn nl‘ RU 486 may lie 25,
`cl’ficinnt as multiple (insc administration. Also, due to
`the long 1“; 0f RU 436 {Tabla 2. rials ll), l9}, single
`close administration might lcnd to suificifintly high
`and prolonged serum icycls of RU 486 to chain:
`saturation of the pl‘ngesierone receptors. In additian,
`in order to avoid possible misuse of RU 486 {3}, single
`dose: administration of the compound would be. prai—
`erahle. On the other hand, ll‘tli clinical potency of the
`single dose asiminisiraiicm at" RU 486 declined from
`89% in pregnancies Omens than 5 wnsks amsnorrhoca
`in 58% when the duration (if pregnancy exceeded 6
`weeks {7}. Thai‘sfarc mnliiplc (lOSSC administraiinng of
`EU 4% might be needed in more advanced prega
`nanciesi
`
`Previnnsly, with daily closes of 58 mg or above, the
`abortifntti-sni properties of EU.)- 48!?) have been re.—
`pnrtetti E0
`lac}: dose-dependency {3—45}. Follnwing
`multiple daily administration of lili) mg or more. Of
`RU 436, the Cm:s were similar during the treatment
`period. {Table i). This phenamenon is partly due [0
`saturation of the. specific serum transport capacity for
`RU 486. and affective mntabolism 0f the: compound
`[8} 'l‘hcrnl‘sre. due to saturatkm o-l~ thn serum binding,
`
`NEPTUNE GENERICS — Ex. 1013
`
`Page 4
`
`NEPTUNE GENERICS – Ex. 1013
`Page 4
`
`
`
`Phamacakineiics as" RU 436
`
`‘25
`
`capaciiy for RU 485 {Fig 2, ref. S}, the Quaxatitaiian
`of RU 486 in 552mm foiflowing intake 9f dams: cxcsed~
`Eng 50 mg may me: in very mfamaiive. i: is: cam
`ciaéed shat {mm {he yhamacgkincfic 3mm: of flew,
`afiminfistmifian «3f RU M6 as méativeiy 3:312:33 (3&in
`dew adminigtamci
`(we: sevarai days seem ice he
`afivmxmgeoas.
`
`Aekmwiedgemems»! WM: {a manic {3m Mafia Haukkaw
`maa, Bonus: Skakpfi, 3923:3513 meaim. Kari Kivistfi.
`Pekka Miltaénmfiké. Tapzmi Luukkaimn and Juhaai foiu
`moms;
`fur their 1153;: and wastmcfive criticism 0? this;
`manuscript. Mrs fink Kivi and Mrs Mzsrjzafita: Tevifin are:
`:9 bx: flanked for Mei: «Expert technicaai heip. “flue iinamiai
`supper: mew/idea by the Suomalainen Liéékétisguxa Dunc
`ciacim,
`time Fwd Faundation and 1m Malls Foundaimn 55
`graeefixfly ackmwlmigsd. Tm: camera}; data mt necessarily
`raffles: the gmficy of any <35 the funéirxg saurces.
`
`§E¥§R¥Z§E€Efi
`
`l. Kavacg L., 3213 Pd, Rests}: B. A.. Ugocsaai £21. Swami M.
`i... fiygdgman M. ané Ream 33. 5.: ’E‘smizzaiiea of very
`mfly pmgnmcy 9f RU fiséwar: aaxsipmgestafiaaai
`fiskmgmund. Cmfrmgmiw 25% {398%} BMifi.
`2. Vasvast 3‘}. A. M. :mé Easy-sis A. A; Pmiiméaaxy {£53325
`with 13:6 aniépwgesmifinszi campmmd £13486 mi»
`g‘epxismne} Io: intermption 0? early gregmmcy. Farr.
`Sierfl. a“ (1985; 6274532,
`3. Comm: 1%., Le Smut N... Uimemn A... Bauiim E. E. and
`Schaissm (in; Taminaiian of early pregnancy by the
`pmgersterone anmgmist RU 436 (mifeprismne). N.
`Engi. .3. Maxi. 33$ {[98:53 iSii-fiwifiég.
`4. Eiigaz‘mn 3'... mad Gdk’nd ‘sa'f. flatly pregnmay §emi«
`maria}: WM: amipmgcstészs: 3 cempaz‘ative minis-é: ksméy
`23? RE} 4859 given in SW? €395: mgfimms find Egastaae.
`Peri. Sim}. «$8 {E9875} 5654370.
`'23: I‘m: ~
`. Cement: 1. “It, Méchéa A. 3'“. am Baird i}.
`ammic
`abmfim;
`iii
`taxi)! pregnancy wéti‘: ma»
`pmgexabgcsz RES 48?; aims at if: somfinaém wish
`pyosiagianéén anahgase {ficmcgwst}. Consmzrapziw: 34
`($936} 4§9~~¢58.
`thmgsts 1).. Mimi! I}. R. 3:, fimnzm 3". F. and Sgsitz
`i. M; Pregnancy Efiminatiefi wiih a his}: and mefiium
`dosage mgimen of RU 486.
`(L'otaimcepzwn 33 (3936}
`455—451.
`
`U’I
`
`6.
`
`7. MM 1).; Uses a? RU 486: a minimi update. FPPF Med.
`83:31. 2!} {39863 {-2.
`8. Rifiikmhcimo 0., ifihtteuméiki 3’. L. A, Kcivmcts 33.,
`Sway: 233.. me31m 1%.. Luakixafinfin ‘3‘. ami L533:-
`teeaméiisé R: Metaiwiifim am} swam Mmiing of RU $235:
`'m \wmen 33m varfiws singk (Eases. £24m £93m}. 2
`(298’?) 379-333.
`
`9. (traumatic H. 3., Spitz I. M... Saivatima A. M. and
`Bardin W. (3.; ”m demanstmtien if file amipmgestiu
`effects <21“le 485 when aflminisfiemd m :31: 31mg:
`timing MES-«imam pmxafiapmgmmcy. in He 13mg?
`gwgesfin Siamid RE; gggg. 53mg Emma Pas £252}: {Swim}
`{Edited 33y 3. fl. fianiieu :mé S. 3. Segafi}, Maxim}! Frags,
`New Mask US$35} pp. 2:33:46?
`it}. Eaikigheémfi ‘53.. Tex-flit: M Shsxupe 83., (Bromita H.
`aad Liktmmééki R: Qtsamitaiéan ai‘ RU 436 in harem:
`piagma 3:33; KPH:
`am? REA afief mimmzx aim»
`maiograpky. {Imzmcegrim 3&3 {i986} 613—624..
`H. Banagna x, Bertagfia (3.. Luzon 14”., Emma} 3.~M.
`and {Eil'ai'd 241: 73:95 new smvéfi amiss: RU 486 inhibits
`giucmortimitf miss: in man. J. din, Endoer. Mémb. $3
`(1984} 25—23.
`12, Nieman 3... Km, Chrmmss G. R, Kelinar (1., Spitz E. M..
`Nisula B. C, Cutie: G. 3.. Merriam G. F... Eardin C.
`W. and Leriaux E}. L: Sumssl‘m iteaimeni 03' Cush-
`ing‘s syndmme with the glumcgmiwid aniagaflisi RU
`435$. J. dirt. Eifim‘r. Memb. $3 {5983} 336—5M.
`3.3. Mifim‘i i). R15, $303338 33., Emma 33. R. Lamra M..
`Hamnsteua 3., Léhtéemmééki 3’. am Spitz 3.: Term§~
`mam 3f earty gestation with the ami-magegtéa steroid
`RU 486; mmii‘am vemss ism {ix-35c. Commmpfiwa 35
`{198?} 3%?»321.
`M. 53.1an 5. mi Mamet: M; Radioémmuauasmy a)? REF
`48$ 33; $1528 zfimifimgmfin £29m?! RS 486 fifid Hsmw
`Ferfifa’fy {7mm} (Editefi by E. E. Bauiiw 2136 S.
`.3.
`Sega!) Pimazxm Pram, New York (E985) pg}. %»-191.
`ES. Bertagna X” Berzagms C, Laudat M.~i§., Musson
`31.4%., Girard F. and Luzon LP; Emitaz‘ywadrenai
`mamas: to 11m amigmcmemcoifi amen sf RU 435 in
`Cushing’$ syndrome. .1, din. Macy“. Memb. €53
`(1988)
`5396x332.
`it}. Swain: M. 1... W335; {3 Amie A. 3%., Sakai: 3. 25. am}
`Sygeiemm M: Piasma iwels {if sniimageesfin RU £386
`foiéawifig 43:35 afimfinigtmiien a? nszrpregnam am} aariy
`picgmni wc-mm. Cammceptim 34$ (1986} “M83.
`E3". Phéiiber: {1, Mogufismky M Emma: C. Ensigny M,
`and Ponies: 3.; Iafiufiam of human alpha i-acid giyv
`win-main {AAQ} as: phamamkinetics and biniagical
`simivéiy 0:” EM) 486. .Sfxty-Eigizth 3599;511ng 9}" 3.518 flaw
`We Sacéexy, Anabaim, {3A. 1986, AMiwfl 188$.
`18. Hakinheima Q, Kmxmia K, meancs H. Spitz L,
`Luukksainm T. and ifihteemfiki P; Magma cancer»
`{mamas mm mepmr binding of RU 486 and its mamb-
`oiites in hummus. .e". “afraid flasher». M (51987) 279»284.
`E9. Dammit RH Bonnat (1. Busigtiy 7M. Chatclct PK, (Emmy
`(3.9 Momen $15.. Wilmer: 1).. ?0§.tiet 3’. and 331an 3.:
`Phamacokinmm af RU 486.
`in He [timfipmgmzm
`fizarw'é M." 486 cased Human Ferm’ixy (Tammi {mm by
`E. E. Eauicicr 3w fi. 3. Mimi). Mama’s: Pym, Nam Yark
`{EM} F311 1533422,
`
`NEPTUNE GENERICS — Ex. 1013
`
`Page 5
`
`NEPTUNE GENERICS – Ex. 1013
`Page 5
`
`