`Primed in Great Briiain. All rights reserved
`
`Wfiiuéfliififi‘ $3M+Q0fi
`Cepyrigh‘l (if) E989 Fergamen Hess 53k:
`
`EXHIBIT D
`
`PHARMACQKENETECS GE: ’E‘HE
`
`ANTE?RGGESTERGNE RU 486 EN WQMEN
`
`DURING MULTWLE DQSE ADMENESTRATEON
`
`Steroid Kareem: Laberarmsrg Deeerrmem ref Meeker Chemistry. University at” Eieisiniri,
`Heirinké, Finiaeri
`
`05mm Hezrrrmrerrm“
`
`(Rammed 3i chaber i987; receivedjbr prefia'cazfrm 4 July 1983)
`
`SmmarymSerum leveis sf RU 486 were measured by high performance liquid chmmamgraphy
`{HE’LC} foiiowirrg erai intake of 32.5, 25, 59 are E30 mg twice éaiiy (bid) fer 4 ciays¢ 5i} mg bid.
`far ? days, as we}: as a singie «time {if 296 mg 9f RU arse. 'i‘he gsharrrzecekinetics e? REE 4386 were
`are: iieear: were fire deriy dare ef RU 423% was: $882? mg er mere. rhe scrum iereis were simifiar. The
`pharmaeokirserrc behaviaur 0f RU 486 during {he treaimem period was simiiar between the sandy
`subject; whereas rhe eiiminaiion phase pharmacekirzetics showed wide individuai variation. Also
`the mean eiiminaricm phase halfwlifes (ti/z) 0f RU 456 varied from 25.5 tr) 478 h in the groups m"
`difi‘erem regimen, yet the variation between different groups was not starirticairy significem. The
`areas under the concentration curves {AUG} were cakeuiarefi. its the: mumps: rim-see emery {mrfss} the
`AUCfiflmzs éeereased when the administereé dose of RU 486 was firmwares}. The AUngm seen
`after administratien 0f
`Efif} mg bid, K 4:1. {mean : SEM 2: {MS 1;; $.34 grmrsifi‘ x Eafmg} was
`significarzrly (P 4:, {L35} §r>wer
`than the AUCG_,m:s strained with ariminisiratien ef 12.5 mg
`bid. x 4d. {3.49 i $.37 553mm x Int/mg), 25 mg b.i.d. >< 4d. {3.09 i 8.15 ,umoi/i x h/mg). and 56 mg
`bid. x 7d. ((3.72 j; (M1 pmmi/E x hfrng). The AUCBWW obtained by administraréon (sf :3 singie rinse
`of 283mg of RU 486. (3dr) was 0.67 i (12‘ ymoi/l x Err/mg. it is eoneiuded that if muitigfle dose-
`admirristretim of RU 486 $15 preferred, daily administratien of reiarfiveiy Sinai} éoses of RU 486 over
`severai dayr seem to be advantageeus.
`
`mmgmummN
`
`administrarien 9f me cempaund, serum revels of RU
`486 foiiowing varieus regimens were examined.
`
`rxremmm'rrrr;
`
`Ere attempts to terminate early human riregnancy.
`various. regimens 0f the antipmgesterone RU 486
`.
`,.
`.
`have been used. in :he studies puhiished se fer, the
`(i?§%~h§<§_rmy~§lfioGarirlznerhyfiemrrreo
`RS £35,
`averai} SUECCSS rare with treatment perisds cf 3»?
`days. and daily deses of RU 436 ranging fram 58 m ghenyi}; 5m~{preeynyfiestravééfldrem:uone} “we“
`3
`r
`(5, H3 and 5% mg}, {ffl—‘HiRU 486 and the carre~
`4% mg, has varied frem 60 to 85% 11%}. However,
`spending antihedy were kindiy deemed by Reasseiw
`as eiear dose-»-respome correlarien with clinicai per~
`Uciaf Research Center
`(Remairrviiie, France).
`formarme has been fcund {24}. Preliminary reports
`Heaiihy nermaiiy merrstruaiing female voiurrreers,
`Q
`,
`~
`_
`‘
`suggest that: in very early magnesia}; a Barge singie
`aged 3349 5'"? 3315* Wéighmg rem kg? partrcggraieri m
`firm: of RU 486 {ie 686‘ mg} 51$ Ciinicafiy es eifeetive
`the. study
`as muiriere dare admifiisrrafien of are eempmmd {’2}.
`Our earlier vrgrk rm the initiai pharmaeokirrerice of Marliipie dare study finds)
`RU 486 foiiowmg Single era} deses waging Emma 3100
`Groups ingesting 12.5, 25, 50 and 190mg at? RU
`>
`‘
`,
`‘
`_
`to 800 mg revealed that serum levers of RU 486 were
`485 NW: daily {21rd.) for 4 deg/5* and 5:1} mg hrd. for
`generafiy not significantly fiifierem; partiy bfifiease (of
`'3’ days. each “coerastrd .35 Six reiuaxteers. Thus the
`sarurarien 0f the serum binding capacity {gr RU 486.
`and efi'ecrive metabofism of fire enmpourrd {8}. Serum $023.} $3335 m 3U 4861 were 339* 3&9 43?, 361} 3’3“:
`reveie of demerhyiared and hydroxyiamd metabolites
`70(3mg, respeerrreiy. ‘mlumeers WSW arivrsed {‘3 er
`0? RU 4% increased. rriong with the increased dare
`3635‘. RU 485 at EMFEG‘OG and at 2£.00—22.{}{} h-
`foliewing singie orai administration 0f RU 486 in
`begmma cm day 12 0? the lute-3:11 phase {day 9) Of the
`femaie raiumeers {83. Hence, to study the pharmw “Ck éurmg an hCG~rnduced pseudopregrraney {er
`£0“!!ng fig RU 486 in “3ng daring mefitipfle deer:
`details. see ref. ‘3‘}. meme Sampfies were eoiieered fiaiiy
`at 9.3% h erior to ingesrirm of RU 436. in the greups
`-------------------------------------------"WW ingesting RU 486 for 4 days or "3' days, serum samples
`*Adsiress fear cerrespondenee: Sieroid Sesearch ifaboremry, were ggiiecmd fiaiiy 513 w {my 5 0r (gay 7, respectiveiy.
`Deparrmem Of Medical Chsmmm Unrvermy 0f
`Figure 1 depicrs the protoeoi of RU 486 adminis—
`gfigfi" S‘hmummpmgfir 10 A‘ 3} {131,0 Halmm'
`trauma and samp‘a‘e ceileerron. Some Sampies were
`Presented in gram at the Mrs: European (regress cg!" Ewen
`3:59 adhered 3‘ 9.333% 5 during the £2 $33133 faiiewing
`crineiegyr Cemrrhagm, Demnark, 1987'.
`{he eeri i)? RU 436 iidmiuisztratéarr.
`
`221
`
`
`
`22
`
`(35mm firmwares
`
` 1: —<1 12.5fm; 1311111411
`
`.
`
`arm-c 256
`V~o¢ 5L.0.0
`am... 100.0 ..
`mean - SE M
`
`.
`.
`16%
`..
`.1."
`. ix 1..
`.
`.,
`3
`1
`V1
`L. "‘4‘“. \{%1\
`RE
`‘2‘ \
`I.
`"sE
`
`‘x t
`
`\\
`
`\ \\\1. 1
`1
`I. 1
`
`\
`
`.
`
`5
`
`2.5
`
`1:“;
`
`11
`(“R'Vi
`E
`
`one
`ms.
`
`C1025
`
`
`4/7 : GAY
`E RU {”336
`
`
`‘E
`E
`,
`
`ISM/1.0155
`
`Fig. E The 1120161201 at” RU 486 36.331111138311013 1.115.291-
`Eectémt of sewn: sampEes111 the 3111133113212 josestudy
`
`.8z'rtgt’e dare 33316;? {eds}
`
`The greup ingestirtg 21 Sing}: dose 113200111303" RU
`48.6 E11
`the mid-31161113 phase 0313132 eycie ((3-8 days
`after the LEE-surge) consisted of 4 femaEe volunteers.
`Bleed sampEes were eeEEeeted at — 1/2. E).
`‘1. 2. 4. 6
`and 30 E1; thereafter daily 11;) t0 7 days and 011 days
`30 and 34.
`
`Se 111m let/£139. of RU 486 were measured using
`ChromoserbE-commrt
`ehmmetegraphy prim 10
`{11331163316011
`by high perfermanee 31:31:36;
`11:311-0-
`mate”mphy {'EEE’EC) {ME 311 these HE’LCStudies ihe
`ititra~.1116 interassay eeei‘fsme3‘15 61" var"1136611 we:If 6.9
`mi ‘13 5A), respeetiveEy.
`E31 311335. the mneen 11.311011; at RU 486 meagerd an
`
`:iays E44 and E—I foEEewirtg 4 and 7-day treatments
`emgetwer. are referred t0 as le.n The nermalized
`pm
`at1» 31
`under
`the
`serum concatenation cum5
`
`(AI.C, 13%) were ea‘teuiated ever we (image intervai
`E3}; 1121;355:5063st rule.1131‘11g the Cms.‘measured en days
`331116 4 and t‘rtereafer divided by the curresponding
`dose.
`in 5:35 the AUC}. V. was caieuEated by the
`trapezettia3 ruEe. and thereafter divided by the dose.
`311 Emis. 1.311: 6331135633 {15,2} were eaieuéeted {mm the
`seismetxtratiem 131" RU 486 measured E‘etiewirtg termi-
`112113011 at RU 486 admirtistretien. 111113111 3133 330311 the.
`cancentrsatiene of RU 486 titeasured after 24 h
`
`{Dee-way arteEysis (1f variance {ANO‘V‘A} was Itsed
`to assess the difference in AUC and {“3 between the
`groups 03' different regimen. The AUCig Obtained by
`various regimens were thereafter compared ueing the
`Weieh two-tailed Hest. In 1116:; the effect of time and
`
`regimen (13‘ RU 486 011 Cmmzs measured 031 days 1-4
`were evetEtsated using two way ANOVA. The AN-
`OVA; were performed with the Statworks~~~~~
`5122131311133 seftwere (Cricket Software. 3310. 33311336623-
`336112.814. E.3 8.18.}.
`
`REESE] LTS
`
`thute 2 ehews the serum eencezttrattons of RU
`486 (mean + SEM) following are! etimtrtastratien at”
`32.5, 25. 50 and 100mg of RU 4813 11.1.31. for 4 dayg.
`
`o
`
`"'""""'“"""E‘"‘”"
`.1
`
`a.
`
`_
`10
`
`15113373
`
`Fig. 2.3631111. have}; if RU 486 (mean+ SEEM} foEEeWEng
`z<7R8.31.
`80.1116 381311133, cf RU 486 bar} for4
`ingegtiott C1?
`{75338.
`
`311 .38 games the highest mean szs were 33131353111136
`013 1321373.). and they vet‘e E.7I. 2 6 3 6 .3316 3 8311310};3
`‘11 the groups reeeivit1gt2.5. 25, 50 and 306 mg of RE;
`486 E1 1. (E. respectively Fer the first 2 davs of the RU
`486 treatment the Cm gwete at the same EeveE111 the
`groups ingesting“3.
`. SEE 01° 360 mg (13 RU 486 13.1.13.
`'i'hrctsgheut the Study. the Cmin of RU 486 seen after
`the dose 03‘ 12.53 mg 6.1.13.1vere apprcsximateiy halt" :3?
`these. seen after the higher (3653.31; 63’ SEE and 398 Eng
`33.3.13. ("Petite E}.
`the
`ami
`33111131635)
`(01111-111
`The
`ittdirichaE
`331818511I-SEM ($6Eiti meters) serum e<111eentmtio1ts at
`RU 486 103301113113; 7day Etdminisiréitien (11‘ 5533 mg at
`RU 486 6.1.6. are depicted in Fig, 3. Serum EeveEs
`were 5113113131 to those seen after the 4-day treatmettt.
`the highest 31111.36 E...” (if RU 486 (3.13 311310377) was
`measured on (E33, 3. 33131 mean. (:orteentt'ettiens were
`measured ts) remain 21601211 22.2 gimoE/E throughaut the
`7-day treatment. peried. and thereafter they began to
`deeEme {During the treatment perieti the individuai
`CM: 5 (11 RU 486 were simiiar in :18 six VUEuB‘Eéfil’S.
`Hewever,
`the 63113136216611 phase phatmaeekieeties
`showed 3. Wiiifi ratage 63‘ variatiert. The in 61” RE: 486
`131
`these yatiettts was 46.83 :1}; 6.2 33 {mean _+_ SEM)
`{TabEe 2). E13 tremeteer N0. 3, RU 486 wag detectable
`in serum 11;) m 32 days feiiewittg terminatien 31? the
`RU 486 administratien.
`
`in the samptes (:oiEeeted t‘eEiowittg administratien
`
`"1721133113
`Serum concentratiane (y me;A) of RU 486 [mean1 $73M ((1)) failnwmg mgestmn qt E2 5 mg
`
`(D) b1(3 -cr 4 days and 5131111: 6.113301": days (E)
`(A) 25 mg {3}, 55ng (f) and 100111;;
`Day
`‘51
`E:
`i.
`i— .4 (5}
`2.6 i016)
`i
`2.
`:- 4 ({1}
`2.513.415.)
`a
`3.
`i:
`.5116)
`26-1133(61
`1
`4,
`3 i 5(6)
`2.980141%)
`5.
`1.
`1-132. (4)
`363203131}
`6
`9.4i83 (3)
`7
`6.5:GE (31
`
`
`
`{1.1: .1; '3 (5)
`
`
`
`
`
`Phemaeekéneiies cf RU 486
`
`23
`
`caiiy significant variation between the 31/235 measm‘ed
`in the difierem groups.
`
`§§S§CUSSKSN
`
`Variaus era} eases of RU 48:3 have been used in
`
`eiinical work. Large deses 43f “53400 mg of RU 486 are
`:equired for ciinieai amigiucoeamtimid effects; {E i. 12].
`whereas the optimai regimea of RU 43a fer amio
`megestea'ene aciiee eemeina ohseure {ind}.
`fiaéiy
`deaes 135 551} mg 0:" more {3f RU 438% have been used in
`{arevieus eiiniea! studies in meet in :erminaie eariy‘
`humae pregnancy {be}. With two diii'erem regimens:
`(sf RU 486, Le. 25 mg and 56 mg bid. far 7’ days,
`Qdfind and Birgexscn repeated eguai success rates (if
`{LP/E; {4:5, Ueing more strict patient aeieetien and iiaree
`different regimens of RU 4586. namefiy :33 mg em for
`4 days, 56 mg 3 {imes aaiiy far 4 daya. and 438 mg
`daiiy for 2 days, Couzinei at all were abia to terminate
`eariy pregnancy equally in $2, $8 and 85% of their
`patients, respectiveiy {3}. Success rates of 60 and 72%
`yepeztted by (jameree e: (:3. and fig Signage e: 22!.
`feiéowieg ingeation ef ESQ mg eaiiy far 4 days em
`2439 mg daiiy far ‘7 eagle, respeeziveiy, are is: zhe same
`range aa the other eiinieai data pubiished 30 far {5, 6}.
`Recent reports suggest that administa'atéon of RU 43f?
`at {£313}; doses 0f 2:": and 50 mg mighi be en {he
`thresheld {if being efieeiéve fer inductien 0f ueerine
`bieeding er fer iemieaiien a)? eariy pregnancy; re~
`apeeiieeiy EH. meafle, pera. eemmm:.. $3}.
`in previeusiy pubiished ciinieai amides, the serum
`ieveis of RU 436 have been measured by direct REA
`E3, 14, 15}. which aiso measures some of the metabe»
`iites 0f RU 4&6 {i4}. ’i‘he iower precisien and accu:
`may 63" REA at high eeneemraiiem of RU 486 {:e}
`eeuiei expiain e»: higher vaiues obiaineci by ibis
`method (Fig. 4). Due :0 its: higher accuracy at high
`serum levels at” RU 486, the specific HE’LC 1116::th
`was chosen fer the present eludy.
`
`,
`m'fi‘m_ _
`,9 ’
`Rte-$835 $23M Main M
`4.1.
`
`5
`
`x
`
`.
`55%"
`
`°‘
`
`8m“, 1
`2
`gs may 4
`ov-«e 3
`awn-e 5
`on: a $3
`3 Surnames»:
`
`Table 2. AUCQ__.H15 and W219 {mean :1: SEM. (n33 fuilawing ingw
`ties: cf $2.5. 25, 5.9 and moms bid. for 4% daya and 50mg bid. far
`'7 days. Rise “3930“,. and 52.12 {enemas ingesiion of a singie dam
`
`of 2m mg 3a imimfied.
`
`Regimen
`12.5mg me. x M
`25.43 mg bid. x 451
`59.13 mg bid. x 4d
`imam hid. x 411
`59.8 mg bid, x 7’11
`2GB mg single dase
`ANGVA f
`if
`P
`
`2m.
`ave
`{hears}
`{gummy} x himg}
`29.5 $3.615)
`L49 : (3.37 (5}
`25.5. 3 L4 {6)
`1.09 £0.15 (6)
`3H; 1: 4.6 ((5)
`078 i (1.21 (5)
`47.8 '1 ’i.8 (6)
`{3.43 5:; 0,04 (‘6)
`40.9 i 6.2 (5}
`{3.72 i EM} (5}
`29% i; 8.3 (a;
`{1:57 i 0,21 {4}
`E922
`31$?
`6.2%
`in“;
`
`P < 0.025 11.3.
`
`<35 $3 mg of RU 436 hid. fee ’2' (lays. the emcee»
`tfaiiens {3f RU (386 were aim measure-23:? by RiA
`foiiowing
`aha Chromesorb‘greefiumm ehromatw
`graphy as deseribed earlier {1%}. There was a geed
`eerrelation between the serum levels of RU 486
`
`measured by HPLC and REA (Fig. 4):. The emu
`rei-aiiea wefiieicut was 8.92 {H a 89;, ha: a: {he serum
`ecsneentratians
`exceefiieg {£64 gamma R115. gave
`higher vaiues man HPLC. The equaiiee for she iineer
`regressicfi iine was HPLC m 0.55 REA + 6.29;:11193/1.
`Figure 5 depicis the mean concentrations (+ SEM)
`ef RU 436 in few women after single Gmi intake of
`23%} mg 9? RU 486. The peak ieveia of RU 486
`(meat: :3: SEEM :2 4.9 ;§; 3.2 fimeig’i} wen: measured at
`Eh after ingestéen, fifiee the iniiiai redisiribmien
`perioai within 6 h, a piaéeau was reached untii
`24 ii. The mean (4; SEM») eoneemraiien 0f RU 436 ai
`B, 2 and 3 days were
`1.3 i 9.4,
`1.1 i033 and
`(16:33 ameifi, reapeeiiveiy. The I”; 03‘ RU 486
`in fixese aeiajeefis was 29.1 j: 8.3 in {mean i SEMI.
`Tabie 2).
`
`The aerum coneentrafiena Of RU 1:386 measered fer
`the first 7 days in the mda are displayed in Tabie 1.
`in 351 groups of different regimen the highest mean
`{Eminx were measured 3 days after beginning 03" the
`R53 48$ ireatmem. Twenway fiNQVA aici not E33di~
`cake staiéstimiiy ségsaifieant efi‘eeé (if time cm szs
`tneasereai m days i—4 in Kite gmups of simmer}:
`regimen (ANQVAffl L660, (if m 3,133, P = {H .2).
`Table 2 ahows the AUC;§. and tmzs Qi‘ RU 486 in
`23!! the groups eff difi‘erent regimen Studied. (Menaray
`ANQVBQ reveaied statistieaiiy significant aariaiicn in
`the AUSE {F <{ml’5} eaEeuiai‘eii fer the éiifereni.
`gmups. In the mea the fikUCGwmrs decrease& when
`me adminiaiered dose 03" RU 436 was increased, the
`smallest AUCG...” was ebtaineei with the regimen 0f
`HBO mg bid. for 4 days. The AUCQ“,§Z[::S foiiowing
`ingesiism 06' 12.5 mg {P < {2.65}, ‘25.!) mg {P < (MEX?)
`bid. x 4:: ami SQ mg bad, x m {P {film weae
`smiisiieaiiy eigeifieamiy diffeeem when cempared by
`the Weigh Eweotaiied Meat to aim AUC{,_.32R, {030%
`ing ingesiien 03' 109 mg of RU «$86 bid. x 44:1.
`The mean ”2:5; showed a wide range of variatien
`beiween the greases of different RU 486 regimen,
`hewever enenway ANGVA 2335! 1203. indicate statistic
`
`5.3. 3715A~C
`
`
`
`‘1
`
`fi
`
`88
`
`‘5
`
`@m
`
`Fig. 3., The individual (open aymbeis) and mean +~SEM
`(closed aimless} serum comma-axioms of RU 486 foiiewing
`finiake a!" 53 mg {33.1%.
`for 7' days.
`the {W 53“ RU 436
`(mean :SEM} in these veiumeers was 48.9 i :52 E3.
`
`
`
`OSKARI Hsixisimuo
`
`teams!—
`725
`
`///
`
`o
`
`2.5
`
`so
`
`REA
`
`7.5
`
`icio
`
`tidfifilei
`
`oi" HELC and RlA after
`4. Comparison
`Fig.
`Chromosorh’g-colurnn chromatography in the assay of RU
`486 in serum. Serum samples were collected following oral
`intake of 50.0 mg bid. for 7 days. The equation for the
`linear regression line was HPLC m 9.55 REA + 0.29 urnol/l,
`and the correlation eoell’ieient was 0.92 (n : Sill.
`
`Previous work on the pharmacoltinetics of RU 486
`has shown that by increasing El single oral dose from
`lOll to 800 mg. the serum levels of RU 486 cannot be
`greatly elevated {ll}. A similar phenomenon has also
`been reported to occur during multiple dose Edn‘tlfllS-
`trution of the compound {in}. The equal Cm : s of RU
`486 during the treatment period following intake of
`daily doses exceeding 50 mg (Table l.) is at least partly
`explained by saturation of alpha l~aeid glyeoprotein,
`the specific transport protein of RU 486 l8, l7}.
`The
`serum concentrations
`of
`the mono“
`
`dernethylated, didernethylated and hydroxylated me“
`taholites of RU 486 increased significantly when the
`single oral dose of RU 486 was inereased from lllll
`to Bill) mg;
`thus equalling or exceeding the serum
`levels of the parent RU 486 {8]. These metabolites
`hear lower affinities of 9,73% (RU 486 : mill/ii) to
`the human progesterone receptor Elli}. Even though
`the inonodeinethylated and hydroxylated metabolites
`behave as weak unliprogesterones in rat Elli}.
`the
`untiprogestsgenic nature of the metabolites of RU
`486 in humans has not been confirmed. Thus, from
`
`101l
`rescuer.
`
`5;
`i:
`
`2‘09 mg;
`mean . SEM
`
` 4
`
`S
`
`6 days
`
`Fig. 5. Serum concentrations of RU 486 in four female
`volunteers (mean + SEM) following oral intake of a single
`dose of 260 mg of RU 486.
`
`24
`
`3
`g
`
`5K3
`
`25‘
`
`0.
`
`
`
`5/1“
`6
`c /g
`G
`“Sf/3’" °89
`W s
`
`°
`
`3&3
`
`a
`
`”fl/lg
`a:
`er?
`
`the pharmaeoltinetic point of view. the optimal dos-
`.1 ge could he the one leading to the highest serum and
`target
`tissue levels of RU 486:
`the strongest comn
`petitor for the progesterone receptor and the best
`characterized antiprogesterone of these steroids.
`in agreement with previous pharmacolrinetie data
`ill). l6}, 4 and 7ndey treatment with daily doses of ltlfi
`and 290mg of RU 486 resulted in nearly identical
`szs of RU 486 during the treatment period
`(Figs 2 and 3. Tahle i). In the ands the AUCfimmzs
`decreased when the administered dose of RU 486 was
`increased (Table 2'}. The AUCGNM seen after admin-
`istration of Elli) mg hid for 4 days was significantly
`lower than the All’{:0_.m.:s obtained with adminis~
`tration of
`l2.5 mg bid.
`(P <: 0.05). 25 mg bid.
`{P <: 0.005) for 4 days. and 50 mg bid. (P <O.ll5)
`for 7 days. This may further suggest that if multiple
`dose administration of RU 486 is preferred, daily
`administration or"
`relatively
`small
`(ie.
`around
`50400 rug/day) single doses of RU 4-86 might be
`advantageous. This might also decrease possible side-
`etlects of RU 486 associated with high oral doses
`{6, ii}.
`The elimination phase pharmacohiuetics of RU
`486 showed a wide range of individual variation
`(Fig. 3), suggesting large individual variation in the
`capacity to metabolize and excrete RU 486. The
`menu rmzs of RU 486 varied from 25.5 to 47.8 h in
`the groups of different regimens (Table 2}. however
`the variation was not statistically significant.
`A large single (lore of RU 486 lie. 600 mg) has
`been reported to he clinically equally effective as
`multiple dose administration in very early pregnancy
`[7} ”The AUCQW following intake of 2‘. single dose of
`206 mg of RU 486 was in the same range with the
`Alll:fl.,m.:s seen in mds (Table 2')
`indicating that
`single dose administration of RU 486 may he as
`ellicient as multiple dose ndmiuistrution. Also, due to
`the long 1,2 of RU 436 l'l'ahle 2. refs ll), l9}, single
`dose administration might lead to sufficiently high
`and prolonged serum levels of RU 486 to ensure
`saturation of the progesterone receptors. in addition,
`in order to avoid possihle misuse of RU 486 {3], single
`dose administration of the compound would he prel—
`erahle. On the other hand. the clinical potency of the
`single dose administration or" RU 486 declined from
`89% in pregnancies ofless than 5 weelts amenorrhoea
`to 58% when the duration of pregnancy exceeded 6
`weeks {'7'}. Therefore multiple close administrations of
`RU 4% might be needed in more advanced preg—
`nanoies.
`
`Previously, with daily closes of Si) mg or above, the
`athortifucienl properties of RU 486 have been re«
`ported to lack dose-dependency lino}. Following
`multiple daily administration of lilll mg or more of
`RU 486, the Cm : s were similar during the treatment
`period. (Table l). This phenomenon is partly due to
`saturation of the specific serum transport capacity for
`RU 436. and etl'ective metabolism of the compound
`{8}.
`'i‘herel‘ore, due to saturation ol‘ the serum binding
`
`
`
`Fixamamkinetécg 0f RU 486
`
`‘25
`
`sapacizy for RU 486 {Fig 2, ref. 8}, the quantitatian
`0%“ RE 486 in 56mm foiflowing intake of (Maw wager}
`mg 3% mg may was: he very infamaiiw. ii ifi mm
`23mm that {mm the phamacakineiic mint of View,
`afiménfigmfian 0f RU $86 as {giatévefiy 3mm éaéfiy
`dogs gdministemd (we:
`seyeyaé days 36335:} is he
`advaatagews.
`
`Ackmwiedgemmis»! «fish {a {hank 33m Mafia Haukka‘
`maa, gamma Shamgm, Hernia meamw. Mari Kivisté.
`Pek‘sza Liaiizteeenméiké. Tagsmai Luakkaixm: and Jahané 3%»
`women far $22.32: hefip and cansfitwfiw emicism of this;
`manuscript. Mrs ‘E‘qua Kivi and Mrs Mzsrjasixa: “favifin are:
`to 19:: ikaankefi for their expert teeming} help. me financiai
`support providw by the Suomalainen makém‘wum {Emu
`:iacim, the Ford Faundafion and the M3115 Feundatimx i§
`gratefully ackmwledgefi. The: Ciimetlt was mat necessszariiy
`retire: the paiicy of any as" {3% fméing mamas.
`
`REHRENCES
`
`i. Emacs L, $33 341%., Regs}: B. .45... Ugocsai (31.. Swami M.
`i... 3ygc§£man M. ans} Raw: F. 5.: ’E‘en‘némtficn of vet}!
`eafly pregaanay cf RU figéwan azzsipmgestafiwai
`wmgwund. Cmflmepiéass 253 {$9823} 3994“).
`2. Vawast H. A. M. and Hatspcfis A. A; Mammary maxim
`with {he amépmgeszafiami cempmmi RUnéfié (mi~
`Sepxistmze} for interrsaption 9%" early gregtzsmcy. Farr.
`Sierfl. 1% (1985) 627—632.
`3. Couzimzt 53., La Smut N. Uimzmn 1%., Bauiieu B. E. and
`Schaissm (3.: Teminatien of early magmas)“ by the
`progesterone antagonist RU ($86 (mifcprismnc). N.
`3223!. 3'. Mai. 31$ {WM} 15554569.
`4. Béigerrgm L. and Qfiiixzd V: Early pregmmey fiermfi
`mama with amiwegcstms: a ceazapamiiw: ciém‘cai 34:21:33!
`as? W} 485 given in SW9 556$? mgémmfi ami Egastasm.
`Fen. 5:321 M {98?} 563576.
`Camemts i. ii, Méazhie A. i". and Ram}. E}. ”£1: The: ~
`agaeutic
`aberzim;
`iii
`333%)! magmas}; with 22:33»
`ptegasmgesz REE =38§ 330m: at Sr: mmbénafinn wish
`mosfiagimifiézz anaieagzse {fiamcymsx}. Cwflmmys’im: 34
`{35.986} 459458.
`5. Sixtmpe El. Mishefi I}. R. 3:, Emma“ E3. F. and Siam
`i. M: Fregnancy germinatien with a high and maesiium
`dosage regimen of RU 48$, Contraception 33 (E986)
`4.554%.
`
`5)»
`
`7. Eifia 33.: Uses cf RU 486: a clinicai update. IPPF MM.
`Ruff. 23 {”863 F2.
`8. Haikinmimu 63.. ifihmumiki F. L. A” Kcs‘wmm E,
`Swaps 223.. meafiw 3%.. Luakkainais T. and {33%
`{wakméiki 9.: Mafiaimiémx anti serum Mmfing a? RH 48%“:
`is: wgmen afser varimxs singk flaws. Human .Rgpmfi. 2
`(198’?) 3?9--38§.
`
`9. Cmmtm H. 3., Spitz: I. M. Saivatierra A. M. and
`Bardin W. (3.; ”11552 demamtmtian 0f the amigmggstin
`effem (if RU 486 when adminigiemd m the: human
`dating hCGaindxm mudapmgmmy. is. 3%: limb
`gwgesfis Siemid‘ fix?! 43$ magi gym Ferfiié‘ry {3mm}:
`{Eéit-mi 33: E. a. Baniieu am S. 3. Segfi}. Magma Frags.
`New ‘E‘Gfk {$585} {3;}. 263n26‘}.
`Ii}. Heikmheimfi 0.. Twain M. Shame 33., Cream: 3.
`and Léihtwnméki R: stamitaiém: sf RU 48:5 in Emmi
`piasma $33; H3533:
`am? REA afier cohmsz chm»
`maaagmphy. {Emiracegflim 3Q {i936} 5i3—6‘2é.
`IE. 3:31am X, Beriagms {1. Exam: If?“ Emma §.»M.
`am: Shard F; Tits: new stemézzi anaifig RU 485 finhébim
`gincmoztimié amiss: in man. J. ciin. Endocr. Metaé. $3
`(1984) ZS-né’fi.
`12, Nieman L. K... Chrmssacg G. 9., Keiimr C, Spitz E. 1%..
`Nisuia B. (3., Cuilcr (3'. 3.. Merriam G. 3., Email: C.
`W. and Lariaux E). L: §umsssfu§ “segment! 03‘ Cush-
`ing‘s syndmmc with the gluwwriiwid an’wgoaist RU
`485. J. ce'ész. Emiwr. Mama. $3 {3985} 336—546..
`13. Mifiaafi 3. R. it, fihofiw 33., Emma B. F, 13mm M.,
`Hcmnsteizz 3., Léhtesemméfizii P. am Spitz i; Tami»
`natism 8f sari}; gestation with the anfi-gmgagtiz; swméé
`RU 486: maxim}: wrsas ism {31:356. Comraceptima 13$
`{198?} 33‘3—321.
`m. Saimm: 5. am? Mammy: M: Radioimamaamay 6? RE)“
`éflé. in $33.2? smigaimgesién 32mm? RE 4345 and Emma};
`Ferfié‘a’fy {Tsm‘mz’ {Edimd by E E. 33.333333 21316 S.
`.3.
`Sega?) Pistzmm Pam. New Yak {3985) p33. 99-303.
`35. Bamagna 21., Bermgms C, Laudat MAL Russian
`3.4%., Girard F. and [mom LR: Mmimry-vadrenai
`magmas: so the amigiucmomiwid action of RU 486 in
`Cushéng’s. asyndmme. .i, din. Endacr. Memb. 63 {1986)
`539~642
`
`ié. Swain: M. L.. Wang £31.. Awe: A. R, (Sakai; 3. 22. am}
`Bygéeman M.: Magma ieveis {if anfigmgesfin RU £386
`foiiswifig m3: afiministraiian m” nm-gzxegnm: am may
`pzcgnaai women. Centracegsim 34$ ($86} 459483.
`{T}. Phiiibers i}, Mcguéiemky MW 305mm CL, Emigszy M,
`and Ffl§1§§$E 3.: Eafiuazm 0f human aipha Lasid giyv
`wpmtfién MAG} oz: phamamkimtiscs and biaicgécai
`imfivfiy 0%“ iii? 5%. Sfxsngighzh Meeiirsg :3? £339 Efia‘m
`crime Saciesy, Anahaim, {3.45. 21386, Agsifim 1886s.
`18. Heikinheima 0., Kmxmia BL, meattcs H. Spéiz L,
`Lmkkainm T. 3:13 {theenmiki P; Magma macaw
`trasionas aim rampart binding of RU 486 anfi its mamb-
`oiites in hamam. J. Hamid gingham. 35 (£987) 279~~38¢
`H9. Dammit R... Emmi C... Ensign}! 1%, Chateiet R, (Emmy
`C... NEGRMR} M.. Fhiiibem £1. Faitiet 3. ans} Samar: A:
`Phamacekimaicss as“ RE} 486.
`in 2"}29 amalamgeszin
`3:66;in R1} 436 semi {Emma Ferxs'ixy sz‘mf {Béikté by
`E. E. Emfiém’ magi 3. 3. $53329). Pietmm Frag flaw Yam
`E: {198$} :39. 1553422.
`
`