`
`F‘KH‘BT“ E
`
`yhmmawkmmia gmdy QE RU «£86 and its
`metabfiiiteg afmy am} afimmigtmfiam Q§
`singia éflgeg m megnam ami mflfinpmgngm
`wwmem
`
`Yangwgfl flxfl, Zfiiufiau $791,, Cfiaflgwfiai He}? Gumgiyzg 35211333*, Exam
`gin X311, REA Van £ka am}? K. fatherbw
`
`‘1 Shanghai Institute 01‘ Planned E’arémhogd Regaarch, Shanghai; Peopie’s
`Repubhc of China
`3 Speciai ngramme of Rasmmh, Deveicspment and Resmmh Training
`in Human Remeductmn, Warm Hfiaith Orgamxatim‘a, Gengva,
`Switzerland
`
`$ Royai ifi3ostgraduam Medical Schonl, Dumas Road, Londfin, UK.
`
`RU 486 and three: {37‘ its mambofiws‘ {R U 42633 -- .rnonoa'ametfiyi,
`RU 42848 ~ didemethyi, and RU 42698 - hydroxymgmbofiitz} were. deter-
`mined by HPLC in plaxma fmm nine Immpmgnam and 36 pregnant
`wcymezn‘ Each nan-pregnant Subject tack an 0m! {3056 of RU 486
`{'25, 100, 1300 and 600 mg consecutively) Once. per mwsimai cycia
`Si): of the wins women also received a (£033 03‘ .290 mg. The 36
`pregnant women wem z‘andcjmizgd into four groups warhich were. given:
`:1 Single dime Sf 25, 100, 410i“) or 604‘) mg RU £86. Mead salpfes
`were taken up to 120 h aftgr dosing. Peak concentratiam of RU iii“:
`accurmd on mast occasmns wfihm 2 51. Fleming conaantmtmns
`
`at I h and at 24 h increasad in pmpmtmr; to 105; (30536. There- Was a
`nude variabifity {up to ten 1,7‘0361") in the pharmacakl‘natfc parama-
`ters Within Leach (1036 group. Magma {JOHCéfiflti’flu {isms of RU £12635?
`were similar to thaw 0f R U 486 but concentrations 09‘ RU 42848
`and RU £32698 wera much 3014261. A3 With R U 486, $156 piasma Garmen-
`{1121510123 of the metabolites were maintained at high Jamie: far
`
`Submittcd for pubiicatiom Ianuary H, .1993
`Accepted for publication Emu: .18, 3993:
`Address for correspondance: Dr PEA Van Leak, Special Programme: 0% Research,
`Deveiopmem and Research Training in Human chmduction, World Haaith Digs-v
`summon, 1213 Geneva 2?, Switzeriamd
`
`© 1993 B m;tfirwo1'fl}»Heinema1m
`
`C02’} if(3 cepfi13H 1993148, Aug.
`
`133
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 1
`
`NEPTUNE GENERICS – Ex. 1016
`Page 1
`
`

`

`{31’1'111’1‘112’ Articie
`
`11p to 48»??? I1 11f1131 11705111513113 I1111I1'11g5 W318 00115151511: W1'1I1 a rapid
`11181115313511) GIRL? 486 1‘11 RI7 £21133; {01111117111 111‘th sewnd 1111).. thyI group
`3311131113 10 RH 421398 accurmd 111111I1 more 3101»Iv and to a much Jess
`extent 1.311111 15111017111 of the firm II1§3113 1111131111151? 111 I28 110 s11111‘f1-
`111111 (Iifiemm‘es betwe€111
`1I1E: 111111pregnant and 1111331111111 11/131131} 111
`1113111 the pIasma cancezflmtmm 01’ phammmkmenc 11111111111216“
`117’ RH 1186 0110? 1'15 11113111311211139
`
`Keywmds: Miieprigmnfi [RU 486), RU 4813 metabolites, human pharmaco-
`kinetics
`
`imtmductian
`
`RU 486 [mficprismnm I7fi-hyd1‘0xy—11{H4~3imethy1amincphcnyl}n1701—
`(l—pmpyny}3mama-4'3,9-111511-31‘11113} is 111.101.5111: antipmgastatmna] 5111111113 {3,}
`which has begin Shawn to be effective in terminating early pmgnanc‘y,
`especiaiiy in co111bination with :1 progtagiandin {2—5}. Thrat‘: metabolitss
`of RU 4-86 have been, identified (Fig. 1 )1 The compound undcrgues demeth—
`31111111311 10 give the: 1110110~ [RU 42633} and dip (RU 428483 denmthylatsd
`derivatives 111-; wail as 11311110113113th vi the pmpy’flyi group {RU 426983.
`RU 486 3113 its 1111211111me can be readily assayed in binned by HPLC {63,
`
`RU 436
`
`RU 421696
`
`szzzC- ---- 11112011
`
` "‘CEEcM-crsa
`
`.....................flu
`
`U” 3
`
`I v“
`
`04
`
`RU 42833
`
`RU 428415
`,
`
`FEGUHE 1. RU 485 and its threr-j meiaboiites assayed in the present siudy.
`
`iQ
`
`12
`I
`
`I134
`
`(30.111111131311111111 1993:48, Aug
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 2
`
`NEPTUNE GENERICS – Ex. 1016
`Page 2
`
`

`

`Mifeprismmz {RU 486) pharmacakirietics: Sh: at iii.
`
`and infrirmatifln is avaiiabie regarding the Mood cancenttarmm of tin:
`three metabolites in nonnpregnant womizn (74)}. The results of them stuii~
`fies Siiggast that the pharmamkiiistics sf RU 486 vary draperiding Oil the.
`(i835 given, probabiy because the (30313901in binds in a high atfinity~iim»
`itcd capacity binding protein in serum {8}. The absance of a propmtinnai
`increasg iii Ehfi plasma concentratim‘isr Of RU 486 {allowing ingegtiori of
`larger times may axpiain the. lack {sf 3. dosersspcnss reiationsihip Witt-tn.
`tits drug is used aim“: for the terminatim‘i of early pmgnancy {18%.
`In arder t0 further examine. the iiiiarmamkirrttics of RU 486, the blood
`leveis (if the parent campeur‘rd and its tinge main metabniitas were. misa—
`surtri by HPLC aimr administratian of various £10385 t0 the same gramp
`of flair—pregnant women, and the. derived pharmamkinetic parameters
`compamd ti‘i thaSe ftiund in pregnant Wtameii {skiing similar dOSES oi the
`antipmgastiii.
`
`Siiiriccrs arid Meriimig
`
`Permisgion far the study had been granted by the Ethics Committees of
`thr: Shanghai Institute for Pianriisd Parsritiiood Research and. of thf: World
`.E-isalth Organization, and informed camera: WAS obtained {mm that: 'vriiiiri—
`tests after the. purports (if the study and the prticcdur‘es invaivad had been
`explained,
`Nine, flfii’l'pffigfiant and 36 pregnant women wcre rscruiter‘i. All subjects
`was healthy with m“: hismty of fiver, term}, cardiavascuim‘ 0r Endgcrine
`disease and none had taken any steroid-centairiing drugs for at least three
`months. The noripi‘egimnt subjects had had 110mm} meristruai cycles 12C—
`;35 days} for at it‘ast three mairitiis prim t0 Eidi‘i‘iiSSiG-fl to the study. The:
`pregnant Subjects also had had regular menstrual cycles {25-35 days} for
`at Emst three, manthg prior to Cfififlfiptiflfl and, at the time Of study, had
`bean amenurr‘hoeir: for up to 49 days with arr ultrasmmgmphicaliy arm--
`firmed, rmrmai intrauterine pregriancy.
`Each non-pragtiant subiect rammed. :a. rims: of RU 486 mica per menstrual
`cycle, three days befati: the fixpttirsd time. 0531116115368. The. rinses, adminis-
`tered consecutiveiy, write 25, EGO, 480 and 680 mg. in six iii the. fiiflfl
`warnerr, a dross of 280 mg was aisu given, Tbs pregnant subjects were
`randomized into fmir groups which were givcn a single (i036 (ii 25, 100,
`400 Or (5300 trig RU 486. The pr‘egitancies ware terminated by vacuum
`aspiratimi after wiiection of the: least biaod sample.
`in bath prsgnam and non—pregnant warrirtn, bland sampies wars taken
`{win an antscubitai vein immadiareiy before and 23 min, 49 min, i, 2,
`4, 8, 12, 48, 72, 96 and iii} 11 after administratian of RE] 486. Heparin
`was used as anticoagiiiarit and the plasma obtained artfit centriiugatimr
`wag StOIE’d at flflfli‘. until armiysed.
`RU 486 arid its three. irretaboiiies were firstsrmiimd in the. piasma sam—
`
`Contmceptjtiti 1993 :48, Aug.
`
`i353
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 3
`
`NEPTUNE GENERICS – Ex. 1016
`Page 3
`
`

`

`)
`y‘.)5?“Mom? AIU‘CEE
`
`pies by H1315 as defimibed pmvmugiy {6) with minor modificatimls. An
`ODS reversed phase coiumn {200mm x 3.5mm 11)} was used with a msbiia
`phase of math-anal: methylcyanide: water {42:
`’28: 3G by V01} at a flaw
`raft: 0f 1 mE/min. Recoveries 3% R U 486 and its thl'flf: mamboiitas RU 42633,
`RU 42698 and EU 42848 were: 92‘3/5, 93%,. $4% and 6&‘3/0, mspectiveiy, the
`sensitivity 13? (lemming far the faur Steroids in piasma was M) ng/ml, and
`the mug» and intfimssay aflfifficiems of variaticn wen: < 10%. Adequatf:
`separation of the four steroida was achiéived as iiiustrated in Fig. 2‘
`Piasma RU 486 cancemmtion-time curves were analysed by the item-
`tive methmi. With dimes; of 200 mg 01' 1635, tha mnvas were, in agrafiment
`with a twowwmpafimem Span mudgi, whereas with higher doses, gem—
`m‘der kinetics agplied for a period Of 2113014: 48 h after cmnpletia‘m 0f the
`absorptmn and digtrib’ution phaSes. Accgrdingiy, the vath war: cam»
`puted accurdmg 1:0 :1 non-compartment madei £11,312). Clearance {Ci} was
`cakulatmfi {mm {EQSEJ’AUC iawa under the plasma wacentmtion-nma
`curvcs chi-aimed by the trapezoid rule), Volume 0f distribution {Vdi was
`caicuhmd {mm Cix’kei.
`
`Statistica}. analysis was dame by t-test and difiemnces was wasidmsd
`significant if P < {105‘ Becausa of the size Of this dose groups mine women),
`
`?07
`
`"STOP
`
`FIGURE :2. HPLC of PM 486 arid its mmafiboiizefi (3.: RH 5125548; b: RU 426953; i3: RU 42633; CE: RU 486): A:
`biank piasma; 53: biank péasma with standards added; (3: piasma abtained eight hours after a single dose of
`100 mg RU 486.
`
`136
`
`szimcepiicm 199253148, Aug“
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 4
`
`NEPTUNE GENERICS – Ex. 1016
`Page 4
`
`

`

`Mifepflgmne (RU 5586,} pharmamkiaeties: Sin 5: (If.
`
`the study ceuid be expected is demonenate differences between groups.
`of abeut
`3. SD {95% level ewe-tailed teet; 90% power}. Based. 0n our
`prevmus wmk {6),
`this discriminatery pewer wenid be sufficient m
`demgn- Strete diffieremeee in phammegkmetie pm‘ametem 0f biuiegieai
`relevance.
`
`Reeuite
`
`Characteristics 0f subjects;
`
`There were :10 Significant differences in physical characteristics between
`{he gm'ups studied {Table 13.
`
`Plasma 161/835 of RU 486 and its membofites
`
`Mega} plasma eeneemratiem 0f RU 486 and its three metaimhees at vari»
`{ms times after oral administration of. single deees mi RU 486 to. the nan."
`pregnant wemen are Shawn in Fig. 3A. Absmptian 0E RU 486 was rapid,
`33 iflustmted by the presence {pf detectable amaunts 0f the stemid in 311
`29 min samples. (9f 31} subjects except «me who reeeivea’i 3 '25 mg dose.
`The rapiciity of abserptien was also shown by the finding that peak piasma
`seneemrations were achieveé at 1 h M Eess for 22.1 of the 42. administratmns
`
`0f RU 486, between 1 and. 2. h fer 15 administraiiens and after 2 h in 0131};
`Six. There was a very marked betweemsuhieet varigtkm in the piaema
`eeneemmeione after the same rinse 0f RU 486, and exampies 0f the size
`(if this variatian are given f0: 30:11:: sampfic timeg in Table 2. Deteetahle
`Eevels ef RU 486 were found in the 96 h samples 0% all women receiving
`283 mg or mere, in seven of the nine samples after 190 mg, but in mane
`m‘ the samples after the 25 mg daee.
`The ratio 035 the 12112441 caneemratiens far the five. doses Of RU 486
`
`decreased with increase in dose {25 mg, 5.8,- 190 mg, 3.5,- ZZQG mg, 2.9;
`400 mg, 1.6; 60%} mg, 2.4) suggesting that the rate of metaboiism decreased
`with increase in dose. This is aiso suggested by the data in fig. 3A where
`
`Phyeicai chafacieristiee Of subjects (X t SE}
`TABLE 1.
`
`
`Non—
`
`pregnant
`
`25—506
`
`{Jase (mg;-
`
`Pregnant
`
`25
`
`100
`
`
`400
`
`606
`
`Age (we)
`Height (cm)
`Weight (kg)
`Body mase index
`
`283 rt 5,?
`159.8 : 4.?
`55.4 4- 37.0
`231.? i 2'?
`
`291 a: 3.8
`181.7 x 1.5
`545 :t 4.4
`2i} 7 i 1 7
`
`26.1 .4: 5.5
`152.4 : 3.8
`523 :3. 4 2
`19.8 : i 7
`
`28.7 :2: 4.6
`161.4 : 3.8
`51.? 1*: 5.3
`19.8 i 1.5
`
`30.2 : 4.8
`38’“) j: 2.?
`53.5 1‘: 4.4
`26.5 :t 1.3
`
`Camraeepzjon 1993:48, Aug.
`
`13,7
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 5
`
`NEPTUNE GENERICS – Ex. 1016
`Page 5
`
`

`

`€12?wa Amide
`
`?W_ ,,,,,,,,,,,,,,,,,,,
`E A
`i
`
`
`, _
`..........
`K
`_
`-
`,,,,,,
`
`W 3,000 -
`«2'3
`5 1.500
`a
`2
`.
`g 500
`:5“
`(E
`
`“
`
`““M‘?“
`
`RU 482?
`
`)
`
`T
`*5‘:
`
`
`______u__L__fl/
`*
`.‘
`.
`.
`.
`Ea
`.zn
`.
`."L
`J__
`
`24
`£38
`.72
`£35
`129
`12
`«i
`8
`
`TIME {HRS} AFTER ADR‘EENISTRATJON
`
`2
`
`1
`
`,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,W T
`
`RU 42633
`
`‘90963
`
`
`____._._____4 A......A“
`VVfif} .72
`
`E2
`
`U Q
`
`E
`’55Q.
`
`
`
`
`
`PLASMACONCENTRATEON(NG/‘MLE
`
`:
`E?
`E 100
`
`200
`
`TEME (HRS; AFTER ADMQNESTRATIGN
`
`FsGURE 3A~D; Mean {SEM} mncentfafiuns of RU 435 {A} and its metabeiiies (RU 42633: B; RU 4284B: (3; RU
`425%: D) afim ma! adminiszrafion 0? various doses of RU 486 to non—pregnam women.
`PM“: 25 mg; g~~~~~g: 109 mg; D~.—fi: 201) mg; c-~--«: 4439 mg: V»~-V: 600 mg)
`
`fer the higher iiGSCS, in contrast with the iuwer duses, the steady decrease
`in plasma Eevds continues up :0 96 , 120 h‘ Althuugh increasing the: dcsa
`of RU 486 ied to an increase in its maan plasma cancemmtimng, this
`increase appeared, unrelated £0 51089;. Thus, the mtius of plasma concentra-
`tmns at E E1 for file 2.5, 180, “MG, 406 and 680 mg doses- wera 1: 1.9: 2.1:
`
`138
`
`Contracaptiim i993fi-18, Aug.
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 6
`
`NEPTUNE GENERICS – Ex. 1016
`Page 6
`
`

`

`fiffifeprismne (R U 486} pharmacakmeiics:
`
`Shi et a}.
`
`--
`
`‘
`
`"
`
`ngaxm
`
`L
`
`I
`
`
`
`E
`
`200 I
`
`5043
`
`
`
`
`
`PLASMACONCENTRATQN(NGNL)
`
`
`
`
`
`PLASMACONCENTRATEON{NGML}
`
`"a 0CC)
`
`()11:}
`
`m3r
`
`i
`
`2
`
`4
`
`48
`24
`12
`8
`“ME iHRS} AFFER ADMENISTRATiON
`
`?2
`
`96
`
`123
`
`
`
`
`R U 42893
`
`“Us”.
`
`
`
`‘ _._..;___mm...L.._flmm_mmmm4m_/W
`‘1
`2
`1‘1
`3
`1 2
`3%
`48
`
`72
`
`4+»
`€56
`
`1 20
`
`T EM E (HHS) AFTER ADMEN ESTRATEON
`
`Rama 3 {amid}.
`
`TABLE 2. Between-subjeci variation in piasma RU 486 cancentra’timg. Vaiues are minimum and maximum
`concenirafiom (rag/m!) at mu: seiected times afier administramn of the various deses 0f RU 485 t0 nan-pregnant
`weman
`
`
`{34359 {mg}
`
`:25
`
`100
`
`201)
`
`490
`
`69%}
`
`37-“? 469
`73m? 088
`1 iii-“858
`T5487
`G»—301
`Téme 20 min
`1280-2966
`41?---2§43
`7?Q---1840
`123—2089
`594 29f)
`‘E h
`548—1325
`583*124g
`318~Ti3737
`358—716
`HES-«319
`8 h
`452-4 (383
`241-—~?88
`97-»520
`8§~291
`31*? 03
`48> )1
`
`
`Camrmepiirm £99324 , Aug.
`
`E39
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 7
`
`NEPTUNE GENERICS – Ex. 1016
`Page 7
`
`

`

`Clinical Article
`
`2.6: 3.2 compared to (10536 tatles at l: 4: 8: 16: 13.4. liewever, there were.
`Significant mn'elattons between leg (lea-e and 1 l1 plasma eeneentmtitms
`{R 2:998}, and between. (lose. and the Yeti!) 0f plasma mneentmttens at l
`h €R=ll.95). Similarly, there were significant mnelatlens between lug
`dose and 314. la. plasma cenemtmtions {R = (3.98}, and between time: and the
`:3th 0f the plasma. concentratimns at l4 l1 {R2033
`Fig. SB slmws the plasma cancentmtiens 0f the menedemethylated
`metabolite. RU 4-26-33 reached peak levels that were similar if: those 0E
`RU 486, but the eealz was attained mete slowly. Thus, in centtast with
`RU 486, peak; concentrations of RU 4-2633 were reached in less than 2:
`l1
`fer only two of the. 42. administrations at RU 486, {mm 2 to 4 h for 19
`fidm‘llllStt’fithnS: and alter 4 h far '21., Efflfii 4- h after (lasing, mean plasma
`concentratmns (if RU 42633 were greater than those. at RU 486. Deteetgble
`levels at RU 42633 were present in the EMS l1 samples after administratlen
`at 100 mg m- mme at RU 486 3115-. in three of the. nine samples after the
`2:3 mg dose.
`Peale: COHCEI‘HI’aEiDRS at RU 42.848 {Fig 3C} and RU 4.2698 {Fig 3D} were
`only about 25% at those at RU 486 and EU 42633 and assumed much
`later. "Klaus, fat 42, administmtions 0f RU 486; peak coneenttatiem at RU
`£12848 assumed in less than 12 h (m 13 Gecasitme, between l2 and '24 h
`in 20, and between 24 and «:18 E1 in taut. In spite of the lower peak Manama-tra—
`tjcma at RU 42848, detectable levels were. fennel at 96 h in all samples
`except ems. when the dense 0E RU 486 was 100 mg a: more“ The times t0
`reach peak concentrations at RU 42698 were similar to these fer RU
`421633, {manning on six occasmfls in less than 2 h! between 2 and 4 ll {01'
`18 administratlnm and after 4 h Em“ l8. Plasma catmenttmtiens of RU
`42(598 declined mete Gilliam}! than those at RU 43.848; detectable levels
`were pteeent at 96 h in all samples except tme after 200 mg or more of
`RU 486, in only ene of the Samples after 108 mg, and in 11011:: at the
`samples after 2.5 mg.
`Plasma eoneca‘ltratmms 0f RU ctééé alter a single 13ml dose at the cam»
`pound to pregnant women are. shewn in Fig. 4A and were rant significantly
`different from the COIIespendlng values in the non—pregnant subjects.
`Plasma cumentmtiens of the metabelttes are. net presented in detail since
`they toe did 310: (filler sigmifica tlv between the pregnant and unlit—preg-
`mam wetnen. The values for the. sublects receiving the $00 mg, time at
`RU 486: are mmpated in Fig. 4B.
`
`Phatrmacokme tic: pamm stem
`
`The calculated parameters fer various doses of RU 4-86 in pregnant and non-
`pregnant women are summarized in Table 3. For wemen in any particular
`{lease gmup, there was a wide variability {up to ten—tam} m most ml the param-
`eters. Fm.“ Cmax, same at the women in the. 25mg close gmup had values
`
`143
`
`(Itmtmceptlon 1993 :48, Aug.
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 8
`
`NEPTUNE GENERICS – Ex. 1016
`Page 8
`
`

`

`Mifepn‘gtone (R U (186) gharmacokmatz‘cs: Shi 3: a3.
`
`1.0m
`
`
`
`12
`
`a
`
`.7”:
`43
`12’24
`8
`WE (HRS) AFTER ADMENESTRATIGN
`
`96
`
`12::
`
`
`5% R1} 42345:
`
`RU 425%
`
`
`
`
`
`
`
`FLA’SMACDNCENTRAHGN{NGIML}
`
`JENTRATEON{NE/ML)
`
`FLASMAGUN
`
`}2_4
`
`48
`12.24
`B
`TME (HRS) AFTER ADMWSSTRATEON
`
`72995120
`
`HERE“? 4. A, Has-ma cancenirations a? RU 486 afler singie era: (Eases of RU 4% tr} pregnam wmmen.
`a. Piasma mneentraiims af RU 486 am? ins metabeiites after mat administraiifin of 500 mg RU 488 tn pregnant
`W§Efi$§fl .
`
`GQHImcemicm 3993248,. Aug.
`
`141
`
`NEPTUNE GENERICS — EX. 1016
`
`Page 9
`
`NEPTUNE GENERICS – Ex. 1016
`Page 9
`
`

`

`Clinical A
`
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`142
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`Contracepfion 1993148, Aug.
`
`NEPTUNE GENERICS — EX. 1016
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`Page 10
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`NEPTUNE GENERICS – Ex. 1016
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`

`

`Mifepristene {R U 486} phatmacaklnetics;
`
`Shi et a1.
`
`almest as high as Some et these whe received 698 mg. Although T1113):
`showed Wide intersubjeet variation within each time gmup, the mean val~
`net; for the groups were 11m: statistically significantly different. Values lGI
`Same parameters}, egn Cmax and AUC, were eunsistently higher in the man-
`pregnant than in the pregnant women fur similar doses, whereas the reverse
`was the ease for the clearance {Cl} values. The differences, hewevet, were
`net statlstieally significant. Values for ”Feel and Vd were not different be-
`tween the pregnant and nan—pregnant gmups. Whilst it wnulcl he expected
`that vel‘nes fen: Cm a}; and AUC wnulcl increafie with lnerease in time, values
`
`fer Tel, Cl and Vd else did, and the differences between the highest and
`lewest times were statistically signifieam éP < 0.05},
`Dilierencee in the mean Cmax values between the lowest and higheet
`{knee at. RU 486 wete two- tn three—fold, but Em AUC the. difference was
`about tenrfnld. This discrepancy garage heeanse Tel increaeed three” to
`tourlnlc‘i with dose, a change resulting {mm changes in Val and Cl. which
`determine Tel. Both V6: and Cl increased with dose, the inexeage in Vd
`Egbe- to nineteld] being pmpottienately greater than that «of Cl {apprexi-
`mately twoicshl}. The increase in Vd with lime suggests that RU 486
`binds only weakly to plaema platein and that this binding is at limited
`capacity. Clearance also appeared t0 teach a limiting value at 6:05:35 shave
`300 mg and this was probably the majm {enter in (letemnnmg the elevated
`plasma levels of RU 486 over a long duratien. With {lases at RU 486
`greater than 108 mg, plasma levels remained high let up tn 48 h and did.
`net become undetectable far 96 m 129 h,
`
`Calculated parameters for the monedemethyiated [RU 45233), di~de~
`methylated RU 428%} and hydmxy'lated. éRU nil-2698:! metabnlites are
`Shawn in Tables 4, 5 and 6, respectively.
`Values 0f Cmax for RU 42633 were similar to those of RU 486 {Table
`4}, although the peak occurred later {mean Tmax abeut 113 h {or RU 486
`and Ill-.5 t0 5 h fur RU Ill-2633} and, consequently, the serum levels remained
`higher Eat a langer duration. The findings are C(lnslstent with RU 431K333
`being a rapidly formed memhmhte at RU 486x RU 486 was also rapidly
`tranelntmed t0 RU 42698 {mean Tmax about 4 hl ETahle 65 but its hlateau
`eoneenttatlmm were only 3130111:
`'25 % of these at RU 486:? suggeeting that.
`EU 421698 is only a miner metahelite at RU 486. its lawer serum concen—
`trating: was net due w it being more rapidly ntetahnhsetl since its Tel
`was not signifieantly different from that Of RU 486. RU 42848 (Table 5}
`shewed a different pattern fmm the ether metabelltes and teacheé Cmax,
`which was Only about 5% — 263% that at RU 486 and RU 42633, much
`more slnwljv' {mean Tmax gallant 14 hl This suggests that the removal at
`the seemed methyl gmnp is a much slower process than removal of the
`first This glow remnvel at the second methyl gmup aeccmnts fer the.
`much lower plasma mneentmtions of, RU 4284-8, Since the Tel far this
`metahellte was not significantly different from that of RU 42633.
`
`{Stantz‘zzeeptinn 1993;4-8, Anga
`
`£43
`
`NEPTUNE GENERICS — Ex. 1016
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`Page 11
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`NEPTUNE GENERICS – Ex. 1016
`Page 11
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`

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`144
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`Contraceptian 1993248, Aug.
`
`NEPTUNE GENERICS — EX. 1016
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`NEPTUNE GENERICS – Ex. 1016
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`NEPTUNE GENERICS — EX. 1016
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`Page 13
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`NEPTUNE GENERICS – Ex. 1016
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`Contraceptian 1993:48, Aug.
`
`NEPTUNE GENERICS — EX. 1016
`
`Page 14
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`NEPTUNE GENERICS – Ex. 1016
`Page 14
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`

`

`Mliepristone {RU 486) pharmacokmeties: Shi et all,
`
`lllserrsslmr
`
`The pharmacoklnetlcs (3f varieus single deses have been previously {8)
`studied in groups at dillerem nervpregnaht wamen whereas in Our study
`the desert were administered eehseeutlvely to the aame wemen. As lound
`it: most previews imrestigaticms {cf 6}, absorptlerr ml RU 485 was rapid,
`with peak eeneentratlens in most were err occurring between 1 and 2 h,
`irrespective of ClflSEfi. The serum concentratlerrs we leuntl alse agree with
`these reperted previously.
`In a study {83 at four tlillererrt doses of RU 485 {ESQ 430, 600 and 800
`mg}, there were no significant differences in plasma concentrations Within
`the first 43 h. In (3111‘ study, although there was an overlap in the cementra-
`tiens with (laser; at lllll mg and ahflve, the curves fer the mean values; for
`each dese were differentiated This also applied te- the plasma eancentra—
`tltms of the metahelltes with the exception. at the ill--tlfitlfifitl‘t¥léitfifl mm"
`peund. Lahteemmaki er al. (8} hatred that with classes above 100 mg, plasma
`etmeentratiom of RU 486 and the three metahallres shawetl little decrease
`
`during the first 48 h after (letting. Our findings were similar with the
`exception ml the 25 mg glass: when: a definite decrease. had Occurred by
`48 h and levels became undetectable by 96 h, By 129 11, levels after the
`three. higher tlerses {200, 400 and (EGG mg} were still readily measurable.
`Similar findings applied t0 the plasma ceneentratlens 0f the metabolites”
`Tel in Our lnvestlgatien increased with increase in (lose but this may
`he an artifaet clue te the difficulties at“ measuring this parameter accurately
`at the higher dose levels. Our value it): Tel {aheut ‘20 hl in nan—pregnant
`wemen after the ZSnmg tlese agrees with the mean value at aheut 25 h
`regretted in preview studies {Cl 6% using law aliases Ol’ RU 486. If this; is
`the appmxlmate true rate at ellminatien of RU 486,. plasma wheentra times
`after administratlen of higher closes sheuld decline more rapidly than
`they do. lrr bleed, RU 486 binds to an upacicl glymprotem €71};
`this binding
`is weak - values of Val are net so low as t0 suggest tight binding — and it
`is of limited capacity. Consequently, this weak binding is unlikely to
`acmur‘rt for the long duration of the elevateel plasma levels at RU 486.
`The hlhrllttg alse appears t0 he saturated at relatively law em‘teehtrations
`Ol RU 486.
`
`As. pestulated prevleusly {6? en the basis ml- the W, the law clearance
`and the 13:1th higher transfer Cyanstarrt hem the inner to the peripheral
`compartment than from the peripheral t0 inner campartment, the pharma-
`eeltlnetle parameters suggest retentlen at RU 486 in some tissues from.
`which the drug is {ml}? slewly released. This is else sugpm‘tesl by our data
`(m the three major metabolites at RU 486; like the parent compelled,
`these. metahelites alsm maintain high serum concentrations ever extended
`periods but they Show mush lewer binding to the glyeepmtein This
`suggests that the blm‘llng of RU 486 to this protein tloes not play an
`
`Centraeeptitm 1993:48, Aug.
`
`lI-‘l?
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 15
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`NEPTUNE GENERICS – Ex. 1016
`Page 15
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`

`

`Cfinicaf Amide
`
`impi’ii‘tant mle in the law Cieamnce 0f the amtipmgestfin. RU 43-86, and ti)
`an even greater extent the demeihyiated metabolites, are: taken up in viva
`by abdominal adipesa $155113 (13}, thf: concentratign 0i RU 486 m adipase
`tissue 136mg highsr than that in serum, altiimigh E0: tbs metabeiitfis the,
`reverse: is the. cases,“ Cansiaieriiig that in tbs average Subisct :36th adipaafi
`tissue may acmunt fur ahcmt 18% Uni {01:31 bawdy weight; the amenm 0i
`RU 486 iocaiising in this tiSSue": may be, considerabia. After a 11036 (if 200
`mg RU 486, the. Inf-5am mini-t is}: its concaintmiion in abduminai adiposa
`tissue was 44'? ng/g £13}; in a (iii-kg waman, this WQuld equats to {sham
`52 mg. I-iawevsx, this may be a minimai veins: since RH 486 may nfit
`1068,3585: to tha same extant in the various is: daputs in the: body. For
`exampia, in animal experiments with ethynyi estradiai, the pmpm‘timi
`Of the dogs: dstected in varimis Eat depots varied widely, with that in
`mesmitcric fat being about five tifllfiS that in abdflminai £3: {£4}.
`’E‘heri: ware mi significant diff-areiimis in thifi plasma curmfintmtiens 0r
`pharmacokmfitic parametfirs of RU 486 and its metabelites between the
`nan-pregnant and pregnant women.
`The finding that inmaasing me 0103:: GE RU 486:} ham EGG :0 600 mg
`puniucas limb: inc-mass. in its plasma mnmnuatmns for up in .72 1*: might
`suggeat that, clinicai'iy, the. inwer dose Shfiuid be as eiimtive as the highest
`(me. Also, litt‘ic if anything; wriuid pi‘i’ibably be gained by giving muitipie
`doses of RU 486 instfiad of a single: time Recentiy rcpmted data an thg
`efficacy {if difiemm multipie and single doses (if RU 486, used in cam‘hina—
`rim} with the: pmfitaglanfiin ariaiugue gemfipmst fur mnninatimi 0f Early
`pregnancy; suppm‘t {33638 conciusicns {15,16}.
`
`Aaknawieégmems
`
`This iiwsstigatizm received {mammal suppart from the Spficiai Pragmmme
`for RfifSeai‘Ch, Devi-1101311163311: and Resmrch Training in Human Reproduc—
`iian oi the Wefid Health Oi‘gaiiizatifin. Mr B'iang Nab‘xicmg Oi tilt: Shanghai
`institute iii Campus: Tachmflegy assisted with the data anaiysis and
`Mrs Bai Xiu-mei of the: Shanghai institute for Pianmd Parenthood Re—
`search with thc: Hamid assays. Skiiiiui assistance in pregaring the manw
`script fur pubiicatinn was prmrided by Mrs B. Fantairm Tabiets of RU
`486 and misreiim samples iii the cmiipouiid and its mfiabaiites were
`kindly provided by RfiusscLUdaf, Paris, France.
`
`Referencas
`
`L Philibcrt D, Moguiiewsky M, Mary 1 at (if, Pimmmcologicai muffle 0i RU 486
`in animais, Iii: Bauiieii EE, Saga} 8}, eds. The? Antipmgastin Steroid RU 1181.7
`and Human Permit}; Gamma], New York: Picnum Press, E985: 49—68,
`2-. Bygdeman M, Swahn ML. Prtigestsmnfz remptor biockagei Effect on uterine
`csiitractiiity and early pregnancy. Commaepticm £985; 311: 454-31.
`
`E48
`
`Ccmtmcegiimn E993148, Aug.
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 16
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`NEPTUNE GENERICS – Ex. 1016
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`

`Mifeprismne {RU £186} phanmzmkmgzics:
`
`3511'
`
`(-3: a}.
`
`CA3 . Cameron IT, Michic AF, Baird DT. Timrapeui’ic abortion in eafly pregnancy
`with antipmgestogan RU 4% 319m: 01‘ in cmnbmamm with pxustagiandin
`analogua {Gemepmst}. Cmtmmptiam 1986; 34: 4594718.
`4. Dubuis C, 'Eflmann A, Auheny F. at a}. Crmtmgestion par is: RU 486: imérét
`de E’association 2‘1 1m dérivé prostagiandine. C R Acad Sci (Paris) 1988, 336:
`57-61.
`
`3. Fun CR Van Look FFA. Ne'wiy éeveioped wmpeiitive pmgestflona antago-
`nists for ferility control. Front Harm R63 1991; 19: HMS?
`6. He Chang-hai, Shi "Yangwan, Ye. Zhi—hou at a}. Pharmamkinetic study of maiiy
`adminisiered RU 486' in newpregnam wnmfin. {Tantraception 1989,- 43: 449-
`60.
`
`‘4
`
`, Eiieikinhmmo C3, Liihmm mziki FLA, Kaivunfin E at (if. Metabolism and serum
`binding of RU 485 in women after various Singis 93:13:33. P312232 Repmd $9817;
`2: 37985.
`
`8. Léhteenméki P. Hsikinheimfi 0, meatm H 8: a1. Pharmaunkinttics and
`metabolism of RU 486. {Steroid Bmchem 1987; 2?: 859-63.
`9. Cekan S, Acdo AR, Sagerstéen E, Van £0ch PEA, Mesainis E, Templeton A.
`Levels 0f the antipmgastin RU 486 and its metabolites in human binod and
`foiiicuiar fluid foiiowing Grad administration of a Singie siege. Hum Reprod
`1989; 4: i316.
`EU. Van Look PEA, Bygdsman M. Antipmgsstatmnai gremids: a new xiii-11611811011 in
`human Fertility regu‘iatmn. In: Mflfigan S, Cd. Gifford Reviews Of Reproductive
`Bim’ogy. Voiuma 11. Oxfurd: Oxfmd University Press, 1989: 1-63.
`11. Gibaidi M Perrier D. i’harmawkinetics. NE‘W Yark: Hakka-31:, 1982.
`i2. Yamaaka K, Nakagawa '1‘, U110 T. fitatisticai mmmemg in phamlaeokimetics,
`f Pharmacokmet Biapharm 19.78; 6: 547%6.
`13. Heikinheimn O, Haukkamaa M, Léhteenméki 1’. Distribution of RU 486 and
`its aitmmthyiated mambulites in humans. ,1’ Chi} Endocrine} Maj-tub 1989; 68:
`270-5.
`
`E4. Reed ME. Fothrzrby Ii. Mctabalism of ethynylmstmdiei in thc guinsanpig. ,’
`Steroid Bjczchem 1975; 6: 1216.
`E5. Wmid Hfiaith Organization. Fragmmcy termination with mifepristam: and
`gemspxwt; .9; Ilmlticmlter mmgaa’iwn betwacn mpsamd flaws and a Singie
`dose of mifcprmmmfi. Fertfl Stet/1'1 3991;. 56: 321-5153.
`l6. Van Look PEA, mm Herman H. Antipmgestins in futility reguiatmn. Magyar
`Nefiwmaiz La’pia 1992; 55: 215522.
`
`Carzzracepzz‘oa ”93:48,. Aug.
`
`149
`
`NEPTUNE GENERICS — Ex. 1016
`
`Page 17
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`NEPTUNE GENERICS – Ex. 1016
`Page 17
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`