, 1'Eil!fi",Jt'J!lt;:'M '

280x750mm

Cmax .•• ^C t"""".. AUC ... ^c CLlFlWTd (nglmL) (lNI~) (ngo!j#/mL) (mU!N~'fl0JT)

19 z0**, 12.~.2 3.01±2.40 158:1:70 182:!:72

23 s0k*- 37.4±21 1.B4±1.30 396±193 221±143

a: H1HfJcYClosporinCJIJf3:i@:IIl(MODlFIED)(01J!llI: Ncoral" Oral solution)'Ml/~ cyc1osporin)WR(:v10DLFIED)(i9IJ!II1: Neoral'"

Soft Gelatin Capsules)fftl!9/N\>'i':;tf9;W$iroiimus •

b:

ftEIJlilfElMl'1T/Tandemfir.filn'$.(LC/MS/Ms)~Hl}·

, 1'Eil!fi",Jt'J!lt;:'M '

iJl_l!!I~stI<!j/jllClOtlU'ie8'J>II"

•

d : CL/FIWT,. DI!a&W~(f-Jmri!f$·

;UifR§,IBB-tlT* ' it!lf!J.2 mg/dayi'fllt-il'lfJS mg/dayi'flWHHI'\lsiTOlimus~rfn !:j:Ifi{fl.:rf1 <P(trough)iaN'-,S·Hn~6.Q±3.2 ng/mL( n=226)m 13.8±5.9 ng/mL(n=219) 0 lllfflLCIMSIMSn-i*JWiJ!lIffHf.lsirolimusIfiIf1JftH;1a/Jt:!JilAUC ~, ss1:lIlli~I'f.JH . . tt(r=o.96) • ¥;f}(=~ . .!fi

mm~

.

lI.,*H~JIH!lf!6~.((,Jj<,--tcI!.'ll.:tt.M:q, , t£jf;"O\llIUl(t-J~H}JT;-~jq , 1lt~f.iJE:tk~~

,

JIUhiroiimus1)Zf5:*"'1t!nq:.A:l(Ifi.Al:!l*

*!lJtthll~':::fff ·1XieM:l\1lJJiI:(loading do;e)a~,"ii1(maintenaJtCC dosc)B'J::'ffi'lIif' *m;fl}It-JWi)..llr(£-~Pi~jIJill{ttf.l.'iE:JtI;:~t;f rtJltr!.pi!!U~·

Mi:RtiJi!rtJ'NllIlflHIl'lli>jJ... ' i'£g.:X,fiHI!ti:'

~im]jrnusl'(J-'FJ$j*gjjjlj#Mt~:a:wr(t,n)(i5::+~62:t16/N~'

fFif!j!H~m

:

Jf8JiU~fi'lWiJ..~*t#flIfFif!jm~tJIJ~yclosporin;JnJJt:rrM!iU'ilj),~

,

mitlf~Hf.'sirolimust@~.lbfJ"IUD"'F~mJlJ

'

m:~

1ti:ti!:t~i!:tIH!lfH'tH!tml.m3mM~/ViI&#t'iIJtYJJn4 •

17 13

","~f$titlMJ1tJsirolimus;!lInW!WJ

fJ *®-1l1 ( zp. ;l$]f:fI ± t'-II!!:t:! )

( ~~:I!nitft.lfl;~if~~)"~

C

m ...

c

_1m.....

AUC

r ...

c CLlFl\VT d

~ng/mL)

('Nlry) (ng

⁴

,j\!fi?/mL)

(mU'J\lJ;'j/i}ff)

14.4±5.3 2.I2±O.1!4 I 94±78 1 73±50 15.0:14.9 3.46:02.40 230:067

139:063

,:(ffHmcyclosporinD!H~Ift(MODlFlED)(WJoiIJ1:

Neoral'"' OnII Solution )fI]/!£ cyclosporinlf§!!i(MODIFlED)({Y1JoiIJI; Neoral'"'

Soft

Gelatin

CapsulcsH~2Y/J\ft..l:t:J!k~sirolirnus 0

b:

tilI!lRrUIIWffl/Tandem ttmlWh'$(LC/ MS/MS)iflIJ1.:)

·

c '

1'Eil!fi",IIt'J!ltl'1M '

iII_I!!I~9CIl!!I!lIlC"mllI'ie~>II"

•

d :

CL/

I-'/

WT

= iMm;lIftni.1lzDmH$l:!/l.!~1((-J~ii!f$

•

H EI3€!'R!fj}.t!T $ tualG • 2 mg/ day P<J 'Mili J!flJMf[]2 mgt

day~I'fflW.ff.

f\fII!I J'll't'mWWIl P<Jrnsimlimus± Jfn. o:p A'HJ!:il!Jm'

jBlIJ~7.1±3.5

ng/ mL(n=I72)f!l7.5±3. 1 ng/mL(n=179) •

^fIJmLCIMS/MSni~.;;niHH!}ft.lsirolimus~:fno:pJtHJ!:iQl!lfJAUCT' s>1fWi~I'tJIiII~~±

(r

²

=O.85)·

~relta~LM:;Ie"f'jI~tlil:{h=1g~, ::fJQ:@:m.fflfFlW!li0;Hlililm~ti:~, :(£JlUfl";tJ-m~iI;1i{f-]24/N!il0;' ~J...!f.I siroljmusZJ'.I$J:i:£Jtuo:pjfHl!.i!a1!~liJilJillG!JE:V::Wffii(f.)iAm' •

WIII;U~MIi>l A

a

R IRffl J1: ~IH# .IJkyc1n~ror;n

..

1;1&cyclo~fHlrin

.. Y,J.!

4H& ' ·~w'lt

.l:1I9E!?:!'1I.lIi!lJIi'iH# m .z1l'-if.tWi1((,j7fiJ:;}ffllM:!'l!

sirolimus3;:Itntjl.@fIt;aIl(IitM= '

.w~a,!;f::IitIil)*IU6m:r.'R

:

~liln;;nfMJ...ma.m*3:I!fIJ:I!::,I(.J.$E13t, ff~l.~rnZJ5.~:II!::IJQ~irolimu~JtnJ:j:lJ!iff:1li1!{

('l'''lM± mill'''')

f'Fm~;L~1il(~k*J:3()

4--

12/Tti1FJ

2.I±O.7 8.2±4.2

12-24fL1jFJ

2.0±0.8 6.4±3 .0

24-301mfl

2.U±tl.!; :5.3:1:2.:5

S imlimus;Zi/Il. o:J:! Atftt

iAi:frCc.u." (nglrrtL»b

4-

1

2$1FJ 12-24ffaFl 24--36fLIIFl

: 215lli.rnAJjJII:.i1I!AtJ: it

b : tJ.@'/8)Hrrill!~:ltnn.*jf(

8.6:0:3.0

9.0±3.3

9.1 ±3.4

18.6:0:4.0 18.0:03.8 16.3:04.3

i'!6Ji\~fI'-J9f*,f$.ft·HIijA

lila m;tJH

fFi'lUII~.tUJHn cydosporinW'Pif _tJGl:& UlRlMl'I?;[email protected] ~tfllllWsirolimuskrCo.J:j:I

ifi1lf.1A1l' (

~[!I , ~ft.aw.iWil)i!li'lQiT*

:

ill;lilIl&(fJ

1f1ii~1ilre;)"i~!ll j, "'~'J:!I!(fJlIl!Si'1J>

' IT

i'f!t!!tf!Y-JZf'

.t$JJ'ftJit

~sirolimu5.Itn

o:J:!:la{l;lQll (

Zf' ~Jfi« ± ;tg'l~m

)

n:-~

• .:z1'fljg( 0k*J:x. ) :t-6Wl1iJ

6-9@1R 9-12fmFl

SiroiimusZIfu t:pJ'jlif!:iR!!r{ Cmin, {ng/mL »)8 3_6flMMb

6_ 9f!;RC 9_12m.1J'l d

" tJlSliil<JtiIi

b:

n::l09 c: n=11 3 d: n=127

~"Ib1OllmJiIi"'!I1)1J!!!l!

5_ 1:1:2.4 5.

1 ±

2.3 5,0± 2.3 11.8 ±4.2 11.3 ± 5.2 11.2 ± 3.8

IfflJ.lllt~m

: J}fJjJlltlE

1lttf.l~iM~-

WChild-Pugh:»t& $ A ( fl!'lt) -

B ( o:p

IfJ. )

~C(:!IiI!:)

I'f.JIIf

J'}J1lt5'tttl~

A (lffJ1Jtft:5!l:1ftm@ 4itttRWiB'

:(£1¥J~#ttf9Hiil1m!M)"IlIlIflJ¥t-oml!flJJl:rn5in)limus 15§:~ ·1'·~m7Ijfi\i!!!!:~IJit:g-HtWff~.ViIlR$~1&¥J.~lt.JlJ~#Il1:·

18fl7:{tttBJg1:~~fI1I8f" Iff lh~~m@:j_A

tf.J

siro1imus.~!RIJ1J~~!IMI(ZjS-~fi1l±m!~:m)

( m - "'llb'nfi"i11Il1

RIM1i~~

15'i}I*')

Cmn.u • 1m....

AUCo... CUF/Wf

;INn

(ngirrtL)

(I."IRi) (nso' HliT/mL) (mL/;J'IIif/i\-ff)

0,82:00.

17

970±272 215± 75

0.84±O.17

1567±<i16

144:062 : l

'lfflLCIMSI

MSifllftJ.

WIJfJ;l;tlElE1It~1tfi;!i!i¥' ffJJJIIE~:tlUMAff.\n~j{f-]siro1irws

AUCZjiI:$:.lfiIl (61 %)&t'IlZjiJ:;}m(43%) ' ifiisirolimu,

CL/F/WTZji~MJ{lj~

{g(33%)' If'j~H~NMfflff.i/JflI':IE-m~a79±12IJ'~:'f' jfijfflJf:qJh~~lf1@iAJilj7ti\'ij.aL 13±41/J-¥~' Iffllil#<1i:li_¥:'f~-e-ax~sirolimus(fJ0:

l&J.!H $ , .lHOJEI:l C"' •

. J!lt...rn~mm1f • ~ifii

'

=-f[<IJPi~ltIijflli(~ff'jOJIlUti!i:1:.1'~(f]S&.* • tBf. '

fN::fil'f1l!iI! UIIf'f:l)JIlB!1fiWiJ...¥J

siro1imus~mJlJ1J* •

IfflifJhElE~I'tJ§t:lit~fI]Ct,ild-Pugh5t*tH'$A(~!l't)

• B(9llft) -

^COli:lft)ItIIffr)Jf!l!:~ffiIfiiA ~lBmll-

- omHfI1:1!:.(f.Jfi:ifflll • W/ffl;tJ fjglE1ft-1Llt:t2'1I<f ' !Jf1Jr' q:.fI -

m:!rIffJ.lJflBHftWJJ...5t»IJltlff:l;tJ~lE11t-i~'i"fff!lifli(f]sirolimus Auc~.t'OJfifi(:»»rjifl'itl:l43%·

94%!l!

189%) •

tt-'F~c"""J::&~ft/fJt

J::l!14

0 M~Iff.Q'JftE5'tm#11fiflVttJm' JlIFJi~sirolimus

t",.Itt:tm'

(t(1ftmil!'iI:!!1l::{f-]ZJ'~sirolimus CL/F/KgUHtIJ~Ut

•

1O!ll!!£ <P ll!8'J1!f mW'! Ill" )"ll.IIlll!1!f mm;",lIlriV- ' I!!Jt"JI'I!l£t-l=cJt;Z -1O( -I-'I'8'J"

ilUIlIflI'i~lOll.lI.ffi

IMlIlO(

2)

I • 1'E1l!

!B'JiIJ1fim'I't.JIffWf!l!:~m1f1:iA:lmmIM1I1fFmJlrn~Ml,.!t!i:· ami'llflJl!l'f.Jff.l)JftE~mWiAliii1l'fFi1I.i'fJitl~fllI.[rnJVJl$m.(2.3)]

• 'Ml1J1m5Hl :

wJjJfJt~m!tsiro1imus!J!m.lllr1J~rntu.ft;j~iRm • fflifii

'

iXiWJt~:n-1ffsirolimusf[:hirolimusrnf-t~~mj>ElINIIIIWHli

(('\1'[2,2%) •

1'E1'!f"m;~IllIilA'ltIl'il'IIll8'Jll1"&I<I'i~lliT-1!!iM!I![!~l!lIIl<lIIli(2)

J •

1j'_QJ>l : Sirolimustt-J4,1!J~i1*4.~ R:I- f\it

to o:plI!:8::I$lM:lif:JlQ

q:.l&~_ifii3K

'

9:.:MI1JUJlinHlI~at 1iil&;lilj!/lR ffl cyelospnrinf{]

corticosteroids •

21tv.Jnlm~j!flJl¥JtW1it ' ~FI~D(lI.rttlil.lfralO-20

ng/mL '

ifii~-fi'loo:mollEli@:~{f-]~:lif:

'

:J:t§t:'!l&(i.lfiLiIlfJl!l~

"i_L5 nelml .•

ji;ijjjtif-Ii'!~j;$l>-ll.m(n=R)

,

;tI;W~:l!fa.~1_7.<;-"l_71 TIlel<l~y(ZP;~Jfit{~$~)({l.OM

. •

(LOI~

meJ1<e '

I_

M+fl_4:t me/m1) : ViDtlf:Iti:s1:.t12-18m(o=14) ,

;1t1i~ftI.LiI:~2.79±1,25 mg/day(-'F.f$Jfill.±t9!$~)(0.053±O.0150

mg/k:g , 1.86±O.61

mglm~) • *flIl:$j·JW :1it(80%)f!m:mBllfilmcyclosporio~16/j'R!illlJlllmfFi'I1lS' J;l.Jlti'Ffi!lllUlJlj.!M'{;!:;l'f.JttJfiJ.JIll:tlR;j~I·

6-11

12-18

..

⁸

^27±10

^52±15

~JiIlf$fjQ1MmB'Jsirolimus!f~.IiJ 1J*~m: (

ZfS .t:,:.lfli'l: ::: tml:t::m )

($-':;'::f!iLJS: • rtn9litlJ!i~itoa,b

22.1±8.9 5.88:04.05

34.5,t; 12,2 2.7± 1.5 10.6:04.3

14.7±8.6

356:0

127

466:0236 214±.

129

136:057 :

Siro1imus€ffjfcyclosporin[::J'Hi~1!t(MOD1AED)(!~l~tl

: Neoral il> Oral

Solution)m/~

cyclosporin1liW (MODIFlED)

(~Ptl :

Ne<>."l'"' Soft GeI,,!in C"psuLes) •

b:

!i!ElJlilHIMm/Tandemfl:lifllln!!;(LaMsfMs)iIJlf~'

e :

pmB".I't,JjjlfM:~{f-]iJ1Im

•

lIHJt~lI'IIlIl:(J.:.s):i!RmI'Mrm-M:(ml)ffilflt:f.lmY-J •

T!'&,rn911.1'$t'£,1i!.ff.lfttt"Ylf!l!:~m

'oittfT>1lffri'fJ/H!f41iiiAI'fr1lf#f'r:}!@WIfJ;ll!J!f1M- '

5- 11

12-18

R:rrn.·1!i;Qt;j=ff:!jl(;]!:!:IJr~~m*!tf;!t.z*WI'!!fM.z I

J

\~f4iRAB'Jsiroli mus~~!lVJ jJ

*4l!:1!l (

lji.l$]fitt:cl\llfi1!~

)

(l'jt-~:It : 1,3,9,15~",*JZPn~RiM;PH:fiitn)M

9

"

1,1:00.5

0.79:1:0.17

,,- ^55±18

*ffi:ffl'nj~jjt*JI\UHfFm.noo:W'eg

511O±450 45O±232

5.4±2.8 4.7;t;1.9

't!40A :

fFmB(f.JI~II!Jfiti!:.:M!.=F-§.'ftJl~ti§rn55J1iitJ;J.t.j~J..' .t;J..?E:~$:~Jt65~J,:J..t.Wi.A.OO'-l'ff.«frnWiA;;LIlfI:I.i!N~Ffl"lS\]&

If!. G5~j:)J:;<:W!J,llf~Hnlf.i:jJ...:(f:t1I:Wn-i'I!l1ilNIIbi~,";j1&' lffiftTlmtrJ.irolimusJtu<Plljgltr!.piftmOOW:18-6~~;ZlilC-if:J...mifM!}I'fJ~*f~

J;( .

11.»1/ '

~t,I;{fJsirolimuslJl!l1f$.It.9.:f1(J,t12%: ~f1!YJsirolimuse-'OlRijRMI'iJ:I!!Jt.kf1e'J'*!tWl:Bi(72.3/j'!Iilr'J61.3/j,~)· ::f~MH.N:!!i!19;

~111Pllm-1'fIl:it

•

f!I~

: m·m

fFi11!fF"lIl!l$J'f~l!i.ti::~nl1cyclosporinF"iJm.Ii3!'" ;MUlJll-'lClJ) (WlHm

: Neoral'"' UraL Solution)ffi/ $:cyclosporin!Ja

(MODIFIED)(j9lj~ Neoral~

Soft Gelatin Capsules){f-];Jt:::JtlJ1&6Jf;;.ilt.W!tjll_JlIflYt*!itM(

14

)] '

::(£~1irfMtlI~rnwrf\fflJ.MWHIl!' ~A

(

190Ul):w~"mA.. (8~2{ll

)If"Jsirolimus'f-

~DlI t:f'

IHliJ1IJ

q:.iftl!l'zllll.M!.1!lIit~I'fJ~"" • .a63eB:~.Ef.l

Sirolimus;ll!*!lI1!tlfS-$CYPJA41ITP-!lf,lgnB(f.JS't':f·

SirolimusWIilJP~l#ffl.:z.~£IIJII¥J~!i~J1trtJ*~B:fFml4JT3I~1'fr~· ~-lHIsil"(llimusOO :nff!Jj~TJlJ/Vij;J;;;LS!~IUl!tr2'lif'FfflIitM'

W Jf.l*iI!);fT •

Cyclosporin :

Cyclosporin;liHmmH!!,~CYP3A4:Wp-!MMBu:J~'il&f!IIm~l'fIl· ll!JIIJMmcyclosporinDII!l~(MOD1AED)m/~cyclosporin

UJ!fi ( MOnTFlEn

)l't-J4/"ItH~ lIIJlB:m ~iTOlirnll~ • S;rol;rn,,~(rtJiAll!t.OOcydo~rorin~'m ffiH~(a '

M1;Ui fFii.'IittR;il;;It",.( Jil.mi* ffl-=

(2)' ~~~lif'FIfl(7.I)J·

,t("J!I!J : i'E~-"J:li!:l¥J~£5Gf.i'Fm:ttl9:rp , 24UL{ij!~~:t(:g~f.itQ:!Ji!~i'f.IJ9.mNcoruL·

Soft Gcllltin Cllpsulcs 3000U,(cydosporinIliA

lMODIFIEDj)~U1BII'!f#' ~WI011;'*'fF~

• . tUflJ·

t4i-*raJU~{*msirolim

..

sfDcyciosporinlJ!lff.mIJE!JFJsirolimus~m~, sirolimusrn~~

CIDU:fitlAUC~}}jIJffl'1ro512%.fDI':'8%·

mUm'

J,aJ:jJHi!N=nll~Surt

Oclali" C ..

,,~u1cs

(cydu.;puri"JWft[MODIFIEDl)HEHIi@1&!:'J+[J;ffltkS!ffl

~J,.sirolimus~;¥

, :fiOOl'lt.mIMRlsirolimusHifMltsc '

flll.irolimuslY-JCmaxftlAUC.IlIJ~f1littt1JD33% •

I-HJI11ftJ!!lJ :

{f~-~.i'fJ!W!iW,SC:1i:fFrnllA.'-f-!' 24(1t.w!Ul~iIA:til<ilf#~WlP1:{tJlEirnNeQraJaSon

lielatin Capsules 3001}>M(cyc!osporin IWIt[ MODIFIED 1

Ht:(I:Y;J'~

,

~w lO:Z'd'*:ffm.P"lmVll~ • ~*[<iJB;'H1rlfsirolimus:IDcyciosporin!ll!IftJJilmURsirolimus~t[J1{I5!

,

sirolimus!f_Ffi~CmaK;j{JAUC:»JjIJtttIJl1116%.m230%· ~jj'jj , !lJ:!~!:;lENcoral~Soft

Gelatin Capsules (eyc1osporine/BiJil MODIFIED J)1J9.

~*I!Y!j'l!.-nl}~!Jt!-f~AsirolimU$R,~

, :t'!Jt!.lII!J1;lfflffiffil1,HH0f2 ' JlJsiroilmusi¥Jc

lIllU

f!lAUc;-}.ijl jfftm37%1!l80% •

iXl\'I.-

·

-

3l3Z1'r'J~£:Q:1Lf'Fm!Jt.ifi '33UiMiJt~i!it:tt5tJlIIIllilJfl7ij1m5~**Jl;mifN.ID!.iIlm.ruilfJ~/Nj;,;~m:m!j\!J;';oo:m7300~a:

Neoral'"

tkRlft (cyc1osporinIflJl [MODIFIED]) • mUfl30011;li.Neoralil> ItXImJt(cyc1osporinlllJ!

[MODIFIED I )i'f:II~q'I'RifllfJlID.mlli'i

'

sirolimus(r;JC...&AUCfI]~.JIlllRmsirolimuslhjffi'lf • ifiim1j,a<';trdJEUtJ,fil.zoq>.l$Jsirolirnus c....fI]AUC:»5.llj~l'fI-!lmHHsiroliTllusH~~ttf1Jll7

126%.fI1141% •

r.>J1Ii'i&~!il1:l'£ffilmNwraI3Soft

Gelatin Capsules(eyclosporinllJ!t[MODIF1ED ])f& llY/j,a;'f -

a!K!fi:i'f!t8P'1IHi{tlJ!fjH~ 'cyclosporin(f]ZP;~J Cu"",flJAUC.M!:mI:!iA~{f-J~'I!f· ~ffii' i'E~JIllI~~RJ...' !lEIrnNeoc"I'"'tll!Ylj'R!jt;l!flh;rolim\ls{f-J~--~J!K!!:!iI:.ifi' ~1!I6flti'FI~' cyc!osporinLlIHl~1i1!1J!Jiti!~t!lltU· rttRil&H~&!mii{n:.l'HtJNeoraIli

Soft Celadn Capsules(cyc!osporinlm A [MOOIFIEO I) ,

l.'m~

flUUifJcyclosporini$llt •

~t)M150m.tf-&!filWJ..mjlftl'f.J~*~:ii:l<t.1j-1

'sirolimus 0.5 - UID3 mg/m'/dayrnllliftJHijSandirnmuncil> On.1 Solution

(cyclosporin OIMi5iii; 1.25 mgfkg/day • WJ:¥t~!Hffl

FFifliliffi"!H1rlflcyciosporin!li'f

lt~

,

sirolim\)sr*fflcyciosporinclli'jlf.Ff>·~JsirolimusMlUJ,;rtnO::PiJI!H'

..

tttIm67%~86%· ~Ji(=1'ilUll'l"'lsirulim\)smUtw:q:.i/I!!r!!H·4tt(%!!~(onl!'

%CV)lfilllftl39.7%3!.68.7%

· *::t<~.R(fJ$irolimusllft=-fM

~~.N!roSandimmuneil>

Oral Solution(cydosporin[:]mii5$l)H1:!¥Jcydosporin./ii{g;ItnrjllAlt •

~fffi

'

%Cvtt1i:mll<t1$:fflf~fa*ifIi(1:t

85.9%:¥155%) •

Diltiazem : Di1tiazem~CYPJA4f1]P-gpl't-J~W&mJru~\!I1I

:

;fiIi1lP~t!J:'~ldiltiazemH~ , !i!liiHllsirolimus!!u.¢Ii1l1l!l ' ^·f.~R;~ ,

P1!ir.iI'birolimus (f(Jmil:l

J!.!j1JJ~1Lrrm(7.4)

1 •

+i\UI!mJJt:¥t/lit~·l<ijIlifDIMf:\tWI01}H'.sirolirnusP"iJll:lil,,"&1201}~diltiaz.em9i¥

'

siro1irnusl'fJ~l!IilJ

m$irijJ]J1lji'fJ12:JIjf3"

.

SirolimusI'fJC .... - ( ....

fOAUC~}jjIJ@"mJmI.4m, 1.3%ilit1.6ffi· Siro1imus::f1!t~'diltiazem!ti:J.:t{-tgnm (deucetyldiLtiuemWde~m"<hyldiLtiaz"rn)(t-J.MJfJ~tl

•

flnftJlf( ErYlhromycin) : l[.~;I!:CYP3A4.fOP-gpi'(]~iI Jl.

.jQ!:tl tflJ :

~

::fllLlsirolirnus0;

milljSlm~*INt~11t ffl

[J!

JfiHt& tt~$I;tl

( 5.17) -

~1'P.I:!C::e::(f"m (

7.2) J •

IriJJi¥DllRke'f241l1{M!:lM~!t.?Nij7<:2~H~i(t-J"irolimu8t*JlIliilHrn:fDmJ\+!r.j800 m81'fJlJ:1lI:~

, /9!

erythromycin

ethylsuccinateti~

•

fftl~tA:fgll#sirolimus-kJ,n:1t*1'f.J1o.ftOJm$IY3Mrn~fllJ;

•

• SirolimusI¥JCmaKf(]

AUC:»jjljtttlJ(J

74.4 - 4.2fff ' mtm...J:tt1JU70.411'~ • fi[fIIt~(r\]C .... f[]AUC-u!_7}i.lIJtti1lD71.6ml.7{g 'mit ... J:tt1JU70.yNl:r •

Keloconmale' KctoconazolefHii~Jrr:1CYP3A4:mP-gpJ!:pllllJJ!!II

: mmsirolimusP"lf:RillJ!fjfUi;lM::fnJWketoconazolefJtJll(Ji.Wm&tt:«m:

Jl'I(5.17) ,

M!~..\~1l:f'FI'I'I(7,2)

J •

~*~.it:t2:JI!ketoconazolefr~.!i1Jtt!~.~JI!.rFtf!tIH:&IY-JIJ&:l&lS!:$&$irotimu~'1Il&r.:1I.m:

' llt---f'f'I'I'IN.

1P.i!:1'£sirotimus{fJCmu '

Imu&AUC.t!lt1.:»11IJttt1m7

4.3(g, 38%'&10.9tEf

· ~jffi' sirolilDusm:U*!lWl(LtI2)]i'!.*~M!· .-"'Jl~

sirolimus3f::f*~.fln::lll!1mU.$+-=/j,a,¥r>Jrnlfrlm.ketoconazole.1ft •

Rifo.mpill : Rifampin;@:li!!IJi'fJCYP3A4mp-gp~w.tflJ

:

:ili'!.;r:ilmfFWl.P'lm:/if/~~~rifampin1rffl • i',HnN!mriflimpinraml'tJ.li!!if

' II!

-:1J!I'~m;!t'E:ft=-fJ;:l:M~WH!Jttrr:J!\f!mr Jl..~,!i.&.tt@:$~(5.17)

• $lim51l[f'Fm(7.2)1

0 +1!]{iLWttJ:~rAif$tJ:)1ea6O)£>:a.

-

~:(A 1'III.¥Jrifampin~~+gg~

, ..zUtJlJlMlfllil---m.m.I'tJ.irolimus 200**, sirolimus,¥]AUCWc", ..

lji.l!:;HHjlj~(lf.82%fI]71% 0

Ver(Jpamil: VelapamilJi::CYP3A4"f[]P-gpI'f.JSlt.'&'.jQ!IjlJ~:

!l!l!iiiJll/siroJimusJiniFlallr '

,e'!B!a;'j!!::JU'i):sirolimusl¥Jtfll:il:[J!Q~~lif'fm

(7 A)l •

~Im 0 ~FU~~~'26MItI!!JJ:W:lit'ifg?2:2!t:H:~{(;Js;rolim"~NJlfHlU[)1 &0

TIlz 1il

1

2/]\H;Ji'fJvera[lamil ' #..fIJE:ltA'ftliH;'i , sirolimusf{]

veniparnilifJ1o.tlInrffl$ijlJAllirn~JIJifjW· SiroHmusr-JC"",~f[]AUC7tjjrJ.I!Jm72.3"f[]2.2f€§' 1fiit"'uMi.:Im.fi{h&~· J:UiU!l!~ftlitt¥J

vC",p<Uni L S( -)titB lHM'11'J¥Jc"

•

• J[]AUC-/ltiithll-r l

.sftt . iliit""",li!${R; 71.2/j-e;j • qJ~sirolimusm=l'J.I§fiillll.gl!i1lJ.~.~

T¥ll9J!!8b~'iroli1Uus'#ffl~' :M:;;KlIJmfilll\.!Iif<'J:JoIIi:tt(fJ!.:-Io/J!lbn~3Z1Lf'l'ifl· Si,oli.-",u,"'~ilH~N!,§I,lffffl '.EI.~.~'1I1'f11Jil'

AcycLovir Awrvastalin Digoxin GLybaride Nifedipine

NorgL:Stn:~1

eihinyl cstradiol( Lo/Ovral"')

Prednisolone

Sulfaructhoxazole/ trirncthoprim (Baclrim-) RIt!!.o5a3:!:::a:tF:m

:M!:::ftfUlfFmS:!Jt!iMl%!:(tJCYP3A4f[]/!il1:p-Spmr.trjm(tmvoriconazole' itrolCona7.ole' erythr omycin' Iclithromycin ' Atclarithromycin

)

'

~liJtlJI'fJCYP3A4.ru/!l.Ii:p-_~pm!Jft'l(

mrifabulin)mmr n

!f~B&ttM:*"lJl(5.17)

- .m32:][i'f.HI (7.2) 1 • •

m)"3f.iIl!Rf~~{f-]CYP3A4 l!lll1iqttrJ~:m!JJ~JPi'j

,

~~JlallfflCYP3A4JlHlirJ!I(;IM'mn~1litnm«t.¥JJ·

fFifI~IfI!%:CYP3A41A~'li:!W:CYP3A4l¥J:tm%rJm:!w::fl')i#\!IlI/#mH!Hl'f'J"t'.-•

:K-EilJf1f-8-

.lftl1~sirolimusl1il

r:pill!t(tJ*"I'fu1!l t8( fil::fIlN:HS:) :

9.iM'r>'(g:iltillllliffil : nicardipine •

tt(!!l:tW~

: cJotrimaroie, f1uconazole •

t;;t~:N'

trolclUldomycin

'

'i!i'/mitttll!VJmI : cisapridc, mctoclopramidc •

J:tftMI!8'I:f : bmmocriptine. cimetidine, danazol,

HJv-j'fi8M~[proleasellJlJ*rj!!fj(f$'Ijmritonavir,

indinavir ) •

It't::nJftE-a-~fitsil"(llimusrrnt:piJm'fI'·.IN!6lii~H8((!i::fm:~)

:

tn:£i!.~

: carbamll1.cpinc, phenobarbital, phenytoin

·

tJt~~:

rifapentine

·

Kfll3!1i6i\-"'l\l]lHH,",

m.FMHrtl"(t~f;o'f:/iCYP3A4Jt

ffi'l'tB:l¥Jf-ti!t4!ii '

~llt::fiiJ#fm

IiiiMi-kbH-.u\?:J;J.liiitiit1:btH'Ffifi:i1UIli1.fJtft!!fl1l

J!m~mlll:(2)

•

~~:~ni 1~1II(73)I'

_ . . iUi3l:a:f'l:JII

SI. John's Wort (hypericurn

perfOnllUrn)@'~"'CYP3A4lJt!P-gp ·1;§f$$iroliTllus;Q!cYP3A4Jt!P-gpfJ~tl

'/f"J;).lIEi.mfFmJltr"JJ!\='tl'OOfflS t.

lohn's

wonWi '

CJf1lZ&fil!;3Si:sirolimusiA1ll:I'"'Hi(rtJi!lr.ftE[Jl.~S!lif'FF!(7.4) 1 •

13 l'ilI"'.1il!

13,1 R!!!tt, R~Wt1&~JII:t.JIa.

*.~~IJ'B"'&*Q,!'t .l:J1!fjjilJii§ttlf-Jii}f~ • ff~WJ;\ +f\I8I(f;Mttlj,B.Q3Jtti:q:.

,

$irolimus~Jit1l30-120fA'i9i;Mi-*2

mgrtilif'.;

It:fflmiil:

(iAm!nl!lI.fiiittJJ) • J

(M:mWljji , K1tl:1fS1100MmI"i'i

'IYH=iI'l1l:il:ftJU;ftllt*:t!WJfJJtt1JUjp,ttif!:e1iiIl"J~1:$'

{±1:P.=1l1iI!]' B

Eil.it.\H:q:.(**'1m~~33!.16rtHiI.!Jflm:

.A.JIlIY:lm:ltfAm-t1:lHi€llt tr) • JUGmMij', • sirolimus!Ji'!lfH!IIJ)fYJI6UfilfUam(ilt:t

^{)1Y-;lJ'I~t:.} 'fii

11M

·1'£104:iJtJ*a~~~:fItflfl:~iIl~),.Im~7C(iI.!mttJl"2 mg({ri;HI~!rul'l1ft.) ,

mrJ{m:*-ftJJl

'

(£m1Hml!i;;m~W5t.martM -CPtif.lt'tJalJljiUm!fu!W!@'II'!!!!~:»fflitltie: " J'B!ilJf"'EtmMII,!fu!IIiM!tt~~7}.ffrartM:· ~IU;(!:II!IP'i'j··B.latm IlB!Mft7tlfr:v:tUG"mJajj{ , sirolimus::fJ.!~OO.f:1: •

ollaN"OOWf:I:*Ja&Mtt;kNljtjjIJr; 101lf&2(ffI'fJAmrntfllJt(

^!ij~211;~

, iltC=*iIij.fRIIt#) •

i'£!'ff:11:*::a~J.Q.

' ffMftt:*::JaCPD!JJ!f6;tl ' Iiff.i:i •

~il:9JJ/m;

• Mffl'if1!i tiiif[]/!il1:i\tPfIH·llliil'f.JW:1'!:; • ffflfttt::*:.S. '

ft!l~JiIJiJif:P§~itfj]

-r'Sj,;:'b·

ff,Jltm!t~MTIUti:rl:y!·ttF.1''±*iiLte"iiJ~' :r£-:lfli/f?1: ⁰ (£4.iM4"~N"!fi.!sirolimusn-}il!:T' "'1I*~~hNIWI'f!J1it(fl'(

iM!!!l!I:1lillifllJF '

IM"J'MvHjfll!tt'~"'

• 14 ilIlflAM

14.1

. BlI5H'a'flH:j;:

fFiN.V<:iJllrrlIM'

1f=fI,J1ilIm,

l!!B

' ~o:p,L... -1MRHt-:J"U~it<\Mo:p, rr-i!!rJlff";]IIUi{HflJf'\ilim:l!fj"Iilf,$ftt'i~~'S:UJ;rr-(!'·J'9:~t':H[]#::&

ttEU1O

·

.i!!!!:8At&;tjl '

1t-t2'-=lim:fill'fJfFW!Iff1"lIEi.lIlftll(.:k:.-~21}iUJ511;~)!fi!al'.athioprine(IIAM:-)~'9::til!fll(IA.=)i'fJt"

tf>'

i!Ullf'JIfli'i/:lHflc)closporin;f{]Sli'llltIiffiM

· 3lI:l@:-;lU1£9:!:I~}R.P'it¥J3I1fh'14!!1Ji.mfj-· 719llLlM"J...,;mA~Jj@· 'M1.ff881rfHt!~r&M"jH}

kll :

284(llliiiA1ltMM:5tret!'t~Jl:i1'fHp,ro.nxm~:7(211;**,fr'-J?ti1:tl!

:

274W:liiiAiY:Ii:MII5tI'f:!fl~rr-i'I!lIltP'l.EUnx"'1ij~511;,f&fI'·Jitl:$!

: fffi -ff IO

lru.fi'-iJ...:Il!:t&3l:

azathioprine 2-3

1}M/~fT/7t(fl'<ftm' 3itM:_.IIlj~{f~Ht

- 1.ru**'

M'l;:1tH:f[]~I!!'!l".t:rl~H'-J34W>1:tll!h.i1!fJ·

.576{iL@!

AlmJ.,.Mlt,

Ml'£agnfj.te.ili'I~gltll:7HJl: 227ffi1iiiA~MI«t7}ftt!.j£~fFl!1I.N/J9.iliJ!11J1ij~2nM:rnitlta: 219ffifiiiA~gt«Ui~fF~

lIP'im:tI&:I'fIl1}J:*50a:i'fJtI-l.

; 11U~-I30m:~.J....JEm¥:~~tflJ·

7£.i1l=fW[i!;Urp

'~~tt.!iemil1MB.E/{Mll!lfI'-J~l.*J.IM$ <

iIm=ftMltt

~<P,~~~~~~mml~~~n~1J>M~@R8'J~~$'~~$~ft~8~~~~ttm"~~(mma~~~~),n~~~.~

>EL: •

T&,rw3iIJfit1~:l<tllSfr'-J::t.Wt«5&:iW#itt;tm:».jfr*8*· :(£;ti;trnMr&f\iIttR • LJ(!azathioprillCra~Hl.frl~!tlJIIJHl.l:t~!ffi

'

~x211;**frl~

x511:**ffff!1.7-jllEi.iiij!l1JitSW.@'WI=f.':It!!.I\1f:Ut9JI!l:~(U~;fJ~' pril!-dl025;tt$>fAlffIl!illt~~lEfki};\£{h.:ffIJll~m~ltJfi!l)· i!t.@- {£6M.Fl ~24ffil.FlIf.¥((-J9<:I&-n1::.$( % /b

,"'iIJ!III'lmlill<~ "iII!III'lIlliill<~

M:R.2:ll*'* t1:x.50**,

(n=284 )

(no::274)

61W1Rm'Ht.J9<:J&.$"

18.7

~"'mJMOI>l

I<lIill"J!t:l\!J!i'(fJ;;'ttY~fF 16,5

M:.f'il!::tJ& 1.1

YEL:: 0,7

1l1Ht:fWiant

0.4

241~1lH!;(fJ~~$

32,'

~IIJ[~!R~

1<lll!il;]!t:l\!1'r(fJ,.ttY~rF 23,6

ntfl.$l<:.l& 3.9

YEL::

4,2

1IIH~MiS¥t:E 1.1

:

1fIjArnJi!i¥mmcyc1osporin.mEl'liDf,'iI~ •

b :

1!!~mWlW1tra~I'fJM.A.

' 'E'll!m'i mill!

16,8 11.3

2,9 1.8 0,7 25.9

\7,5 4,7 3.3 0,4

,"'ilJlIf"'ffllill<~ "",lIfl'lffllill<~

.. 111 m :x.20:M a:x.50k*'

(n--227)

(n::219)

30.0 24.7

3,1 2,2

o

44,1

32.2 6,2

5,7

o

11 '

1fiIJ...!l'IJiM'f#FftcyclosporinflJ&'PtlROOIM

·

b :

(i!t!im~flf.f1tra~rn1PiA

c ' ±'Jl!;',!ji~-mt'l!

25,6 19.2

3,7 V

o

41,6

27.4 7,' 5,9 0,9

Azathioprine 2-30~/0!T

/-:R.

("",

161)

32.3 29.2

25

o

0,6

36,0 32.3

H

o

0,6

47,7 41.5

3.9 2,3

o

54,6

43.9 4.6

5A 0,'

1'E-"1J> '

'UlOnli'll!l8'J1Hliilll!i"j"'f'lI8'J~'ll!"''''~ilil!it:!

'

l''''ffi''ll'I!;(~-1'E1i!-

• = " '

~Tj;(I<=_-'

=c ff- '

WiJ...fI]tHlf1lMl1Sfft8~1e •

tHtl'lmWWiJ...!nflf,5$1:EJi:lf:Illm,g&;fUf.toom: Q!!JIHU(f]

•

fiif'-l!!:Pl:JmlifJil'flJ fFWJ!!f'>'lrnliOlJ'flJ Azathioprine 'tl.'lttm

-li:R.2;f,:**' 'ftf:R.5:&km

2-3~~/~ff/:R.

!>\1i1/

I§lIll!!fiili!f.l j!fl12{fl;1R t(!24fiFf

1~A#mo$

(n=284) (n=274 ) (no::161 )

lil 121ll11l

m24f1?i~

<.14

_

7 85.2 97.2 92.6 (n 227)

89.9 81.1

96.S 9(),3

a : 1f1:i),.IOJffiifJHflcyclosporinfOBl:'lIlJ{1N1J':!

•

b: 1!!~tIil:flfmlt;aI'l'(r~wV,-

<.12_7 89.1 96.0 94,9

(n

21 9 )

9(T9

79.9 95.0 89.5

0;I1J\

9(),I

98.1

%.3

(n

130 ) 87.7

80.8

94,6 9(T8

/iI.!ffl fF

,l~.ru~I't-JWi.';!1W'A',*f.fffitw..ltt2n.~

, fF

m.~!Yt1lia.f!II&m&IStrr:Jtt~1':HJf

fFi'F III

(~m.M-IlI

Jim. )i'fJijifi£$

⁰

tEilitti:- '

~!it-,§"·9i;milfitl~U&ft:»/6:»,m: ff~.~'i1Hlilm2 rng/dayitll.l,mo:pm:Aj~.@rnitl~9<:It1:$jIl:azathioprine7tHR.moj:l~J...

E 'U!\rnrllf«*:J&$tHiJ.::i'

1filfFilUfpqnIHIl~5 mg/daym~Mo:p,~AliJ:i\t\rnfuKt*J&$WJ~1li 0

:ff.lbtla='

~~=8":.tl!.*9i:tH1Iifl~;m

fiJtIli'JtIll '

=1tt~

..

(t;"""II!"ffll"'~i/""'IIl",I!IA",\l\8'Jlt;"'~~$"J"'''''''~IIl<PI!IA'',\l\8'Jlt;'''~~,*,I~(;(

• i>.';'Iil'fI!',

Ajtii.mfQillil'i1l-&t:t'tlfFm.0!N~ilitllfl!i'i "£,aRlI:fljD~W1flJ-M:fl:lflifrtJ1'H&!IlI.fr.Jfltt~JI!1m' i!~=-fl-l&!Iltt;(£f!l!IfIJl;Wf.p.;llB.ilfm5 mg~1Eifl!:!.~f1I[Jl::f.a&M!(5.1)] •

1'E6iWIlH!; •

T-1"ljl]!"(fJ~lIJ!$""llt···

;M1i1/

~A(n=166)

;,I~..w.A(n=553)

liltli1!=

,~..A.(n=66)

~FmtA.(n=51O)

34.9(n=63)

14_

O{n=221)

30.8(n=26) 29. 9(n=20 1) a :

~A[<IJiI#l:lf-meyclosporinf!l8lf1RtIBlM:

•

b : tl1.MWili'j/l1l1:.~mf(]Wi.m

18, 0(no::61) 16.4(no::213)

33.7(n=27) 24.5(n=

I92)

33.3(n=42) 31.9(n=119)

38.5(n=13) 48.7(n=117)

tIHllilitM- ftJilAlil-=cp

, m-Ff~3it-1ffteI2i1JfI]24'R1.F1 (ilitlM- )!JUf!: 12ftl35M.FI (litIa=)~

,

:fljmNankivc111nMJ:t~t.llifj.·ftH£:rnlji

~ ~Ij \.t-~iJI~~!fi ( GFR) • It I:j:o (#

m cyclosporine:fiifFf,!til: P<i llRiIlil'fllzliG J...i'f)Zfi

¥j W IJ ">Jtill~l!l*

1t

fP.IfT cyclo~porin.,Wa:<athioprin"J!l(;

'9:fl~m.z~.A.1li

•

tEtJfitH&1l» ,

fljJ4!Nankivell15;§l:p.:mHnif:Hf,]"~J',*i*;l£Ij.i3!:~

(Zfi~{ta±iWJJit~.5!·

0Nl/7tat )

tfiflmP'lIlliRU'lJ

fFiflIIP'lij:<1i&~j

Azalhioprine

y:~"

~ ~ 4V*2~k*'

m?e5i}k*'

2-30~/0fiI?::

!JI1i1!

12m1FJ 24M.FJ

grt~-=

12fW~

36fW~

57A±1.3

(n",,269) 58.4±1.5 (n=221 ) 52.4±1.5 (n::<211) 48.

1±1.8

(n=

11l3)

a: i!1.tJii!l!JlUf.fl1:.il:ilUl:tJfili)"

b :

fj.$9<:nil:mA(f.JGFRfillllfW.o

54.6±1.3 (n::::248) 52,6±1.5 (no::222) 51.5±1.5

(n:::: I 99)

46.

1±2,0

(no::

ITf)

&1 .1±1.6 (n=149) 62.4±1.9 (n=132)

58.0±2.1 (n:117) 53.4±2.7 (n=

102)

ffiUtft- .fU:¥tta=(t Jm--fWiI':iliU:Il.p '

.¥.:jrfl1:.-;;;:MI!krui1:11J

n

!iffM:f.l~fHJF.fFzWiJ...

'

Jt;fjffl-~tf<ltrZf'J!;:j~/j -lltOl~;i.lH~Jt*

i!t-ft~~ttm:fFz1MJ...fll.·

.fjm:J1IJfI!t/UL5:lIfiJ;J!l'ftMilOC!fl1m{fJWiJ... -

£-;nlIi:OO;U;ffmfm -~.E!.l!;\!iIi~.~'m"Jt!!iVi'UIl;tt:~g:1W$IJB:l!$[

JlW3(}&tt;«.qr>JI(5.8) J • li'ilfllll1l1!' 1'E-rwMil!' :<<P'e"

I'IflIj(f;~"'OIll\'" ""i'lFiIf*"iIiT"'~lU"iIf*I1~I~~Jjji1ili'g;(nl'''J>llS'''Y~IF(fJ'li'''tt lIJfl~1~HUie~-m~'I!H $.n~~!ffl!l!.~( 12.3

) J •

14.2. ~.Ltli!mcyclospor1na'*litl!

tEWiJ..imfiW-1WfHtB3JjIJ4ffllJitfl: f?ltlMl-tfcyclosporin'

-!e.til~mfFmB(f"f.$ttf:t.~Qi:t;(t:j~~tt!llYRAA.(/{l71W#i·

3JtM=':l:iHRHili

/1-~rf1,i:.-' !JWl{f-]ilit!ltfi1JS57m1:fr~ifII

- 1JU#;* -

ltifll(f,]i!!I*~fi 0

:AU.fi525t'tWiAIlW '

mliMA-3'ng~.tfI'fl1J1a~(f.JfFi'I'lIf·

Jltilitlfl8:~;iJ!fjnM*UiH1::ili'!.f!1H.tilif'fFl1t1l

- cyclosporin 'fIl&'llP<J rnJltjlftJjliqA ' J,:J&lift=flI.M

(Me::»mllfllf-J~m)~-'fffi[<iJ.tJ.J it;mffiz*f;Jmcyclos~rin(fJfi}:j.J....-r It:t2 ' Cyciosporin~:S@Wlflil

' fi:i1IlfifJm.nm.¥::IIJllKli£{f-JJi:Io:pltlatiA, i(!'iJi'iIll( 16-24

n~mL

iCr::fL l.M12MJi • fiT*12-20 n g/mL' .l:[email protected]:».ffril!lJ5:Eflfi; ibr-)

·

:{£=1 MfHW' 43oUlWiJ...Mlt5:*P!AAUftfJHfffFi'l'tIlWcycimporin(I'.Jm

~mJ&~yelo<porinp;c..1'tl.ufi:iet.('Fl%[email protected]:m;il:Ufl

•

jl;H+r.tiHttiMKt5tftC~, -E2t8iX~tl.!H}~OO4jj!j~fUj::f;:D~ff:fuJBanff:»mm=Ri;;LM:tl:l=*fF~~Jin'B1If:fFti'

,ItnfflWlAlfi(Serum Crc"lininll):::O mg/dL - lNJtl'f

RJ:lzIj'i}Nmf1fDf:ijl;~cyclosporinrn~1'f(

ElIIlitIl3::t'i'lflllll'i) •

::Elt!I'F.II~t~!WI'!;ffim~-n1\'H!< 12M .Flrnn-lll~:ff.m$· 3:~{hIl'i%!:lWt5mtl!m!;lJJtm¥im1!t'I'f.J.~f:I:~~ff' fiij.A.1'¥~$' ~m;F.:I&:{fJQ~$(~ii£\m*ifl~W:$:lmtm

"tfJ;ffi:ttlMF -

fjfjS~~m -

WZ3tL::) -

yq:ibm~fflI:()t~MU)J~ff.1.:.W~ -

®;t'l:IJFIT- -

fjMl~~m, ~9EL::)"

r!J<l!{~n.fI'ImIJi,!1~J...l'£LtttnIi&12

- 24 -

W36fW.M~ff.mEf,JfflJfa'

P*lifflz-f$MftlWmA..fi.ml'f.Jf1lIJfalt1(l.J

·

~MljiHfii)"'i'fJffm$(%) : gAl18:....:~ fFiffmOOCyclosporin~{tHe~

(n=2

1S)

a

: t!MmWll'jLlti'Ei~!fJ1NA b • HI!il~Wilijjjml

, • fit!i'lI\ftl\1J>lIIllill!

d : fi"?JJatllttlBilifTI¥JJtlJfUl

95.3e

91.6 87.0 97.2 94.4 91.6

Cyciosporin~

..

w:aUI~m

"~I!l!jMl

(n-215)

97.2

94,0

91.6 98.1 95.8 94.0

r~A!l}!!:.m-i'E12W35ffljRB.';' M:x.J,:JJ1I.-ijJJtm~~ttmmn*E* o

@EI3M1t1:»Ml.W:(post-randomization).?E:m

I2!WA{hiil'ij1WMilM..(::

*"-i:!fHfl!tl.~:If.IRH~

•

:*::OO7tMltl:»&a:-B'::t=..nfil!;ttYPFitr~m=:t~1'I •

i1:ltiik;El1i'S36M.FJ!Ii¥--m*tJk;ElIi'i-l;lJ~-:m:'J(j[ttttM'Ftf.Jl!f~$(%)

:

1tt;J}8!=o.b .i; I(Jj

ff:

~1I

OOCyclosporin-€ff#· if:J/it

(n=21~)

rJ!lHl5H .tlJ:1W

!!IlIIillm&3!lil12iJl1 Fl'

t:[email protected]:!.~B'J 12¥lj3G~~FI

!!IlIIill~1J>3!lil36iJl1il 36frj}~;Zt!~r·

a:

t1MWJf'1l:.1NRI'fJ~A b '

1li1liIiTlIIJ!1i'lIllIOlItl"'",,\l\

c ' m:3/WA

±2H~fii!lil.7H!i

9,3

4,2

1,4 5,6 14.9

Cyciosporinf!i'~f&fla!l.!ffl

" '1""!l!!1ll (n-215 )

10.2 9.8 05 10.2

20.~

Rf¥frlllMAffi.

.fi~4(f]::f~C~·f

Am B ItnUt1t:Jf,!

(liLA

mismatch

):{f;cyclosporinfljtM&~

/ft5t'-'Cm

@"i!i&~-fgJnfF(fJlt$IflIltiI'fJl:t~.f";m:

flail!

eyciosporinW~t:i

( L 5.3 %lt3.0%

)

• ffii

)..i:fti3

ItnamW::f1£J;f ,.;:3I'fJR $tinfrllJ,.

*i!f~~tEV~

fi:l1Jlt::t.t£i'Iii'W

ra~m

qr

r& f§i'ilt

~(6.8%f:t7.7%)

•

ff:i'l=fIlYt!Cyclospori.nt5-f#ii:lfiJ.

53.2±

1.5 (n_

20S ) 48.4±

1.7 (n_

203 ) 47.3±1.8 (n _ 196 )

" i'lMIIIMi'lli:lt;Il!"'",A

b:

1It7!m-t!l~tli~M~I&(f.JWiJ...El.l!I'fzJil~~GFR=O.0

, •

ffill,I!<tllli~IIlB1!!!lI1Ol1'I

59.3±1.5 (n

_

2OJ ) 5S.4±1. 6 (n _ 20I ) 58.5±1.9 (n_

I99)

fIJmNankivellnf.,!~Hn~trflW:12

- 24!m36fIMJ=lZGr-R

'l'£cyclosporin~~.MiiI.!I--IlJl;mmf'F~U!lJ;;itlmmml'fJ1ji.jA...;LGr-RiVfMifIi Mfi:ii'tilWeycLosporing.t#~fRm· /altl~Hl.J1IJ:(;j~tEW'.r.:-l¥J~),. ':{£"yclo.porinj.lilJo#.m..LGFR~~fI;if'lII!l!"yclooporing.j)H:il#

til·

M11ll:»tttt&:t¥t~~tttl~fFlfJrM.A.I'f.JGFR ' ~ljmm&flI.u'JHi'I~~ •

.ti!~~!J;{

9cm.!11i'tJ36{3.F1

(f.]1!'~i!;';

'"Ui

~

•

{F,t

1l:.cycLosporin ibtffl'njjlj J...

:(:Efjtfl ~I\

8f.1j.FI

~60t'2I

.FI1'F.lfl!:':& iJ!.l n.m:Hl:3i5m!J'l

1'f.Jfl!f&. f[I

m,

RcyclosporinW~&flJlt~mrr-i'l'tBi'M~'¥]ffiiAql' ~52%(112/215)fiiilA<iJWJ-.'itl!n::I'fJ"'I\U:iII:iMi.i!$(GFR)'

.I:O]HJ.u'J:f;J#H' ttl'r1mAA.

·

14.3. iWi~!UD.P&JllgA

(f-l:Afti9iMI!Q@lJ...(tI1,!'/\\),.

.

1lt5I~ll1:~$~B:'I'1Illi1f$.M~It';::I¥J!rfJ...

. itli{.iLll!lflt!H

pRA = pand rea<.1ive antibudy

,

p:ak. PRA leveL>

80%»jf!ftl¥J-£Frn~Wlit.o:p(!ittarn) ,~jjlj'!ifj~IMAti~~~i4llfFiff.!Jia~j:£tffjl:r-Jcydosporini+la, J!f1l'SM~)"itl1fJt(flt

J:t!!HttJ!lI9lJ) •

f.lijj\I!*(fJ'J.fIIilUHa'lIi:IiJ....fHI'l~!ij{:irr':lI2IWJ"I fI<j , ;fl!!llJ1:tAi~UHitJ.!~JfiiM(r':I~tn:W!!:p-1Iill'+'I!i~~IO-I~

ngfMI(J,:JI!!JIif

5t.t1Tit~iJIlJ) • ff&;fiI'FfUi{trn2~P"l

- 2B2-26MJ - m26-52i']

, ;Mmcyclosporin{h~m:fIIffiWl((·JIii{g;!I;!~Ifni:f:ii.lJ5lm200-300

ng/ mL - 150-200 ngfmL' 100-150 ng/mL

[*RJil6*~MI!~(12,3)1· *~iIA.tn~~t9."P{.,-iiJJ;J.fJUt~itHIIJlRfi::~Nf1fmtJtte:~!.4~$

:

YlB88,4%(fJYiJ.../'l~M:ftI~g;ffiW

•

l1Ilfif.lf~;f!:(£~1iM1'f.J35f11~nfYMo:p{.,lmfj

,

:tt1=f224fllmJ...}gAibtM!tli:m~:¥:Y-~mitiYJ

sirolimusLJi!cyclosporinftmit1lR . J'tifif.i77.2%lfJfiiiI)":@:,!/RJ...'

24.I%ffJfiJ!A;ZIJlJ1fm~i!i'M1Iil.f$.M

'

13.5%lf.IjjiiAmi9ifit:t\!HifiiE

(PRA '" panel reactive

anlibody)(f.J~A· MAfJf(I12MJi~(f]ram;k:J&(~f.ul: -ftUWiiW.l!r!1flM:rr:Ja*''W:ttfj~fF$f.f

- n:ft1l;k:

J&.

~reL:)

-

/ji;f~)j·~fHi'l9<:Rt~7EL:

-

Jl!WJ1.JfJE(fllmNankivel1jj.fjAWjfllif$HtMtI'r'J'Pif!j">lf.ia~oim:,t!(GFR) f'F~f1i9&1¥P(;!:;m

mi ' ""''''%<l!illllU'lliHl!< •

~1iI12i~Il1J>~l!!~~lll<

• nlil$ellJ! '''''roc:

.Rr_tlN"nkivellnf.2:;:t~tlt,'+'!'tJ'M\£II:iII1t!'6iiH$(CiFR

: rnl ./min ) :

1!l'M~

l#fflFFN!r&,

cyclosproin~..s!l.'i1tf1!!itlI (n::<224)

nlJ'($ei&"">EC: ( %)

'NmftE.{zp:f~](,"::I:OOJI!::~m)

a.b

23.2

9,'

52.6.!:1.6

(n=222)

a: fljfflNankivell1;

.m~'tlJWt$-Mf!;:l'fJljif!;J~

IJ

'~1II~J.lt!$(

OFR ) b :

tf;fS;Jd&m)"If.IGFAAUjl~o.

1Il),,/l'1tl1211'l1l1!i8'Jffii'i$Jl!94,6% '

I'l'UIlJ~iII,~ili11!'1<tt~""H"8'J"'<E$f>IH%

' J'l.*llltl"JJl!Il!Ilt.l&;ttlJi''''''If ·

14.4. ~~j!I.IIl!t\!Ca1c1neur1n!lPItiIJlt.Ja~ • • ~.M5A.t-a'jS.m±..~mmJlM.~

[email protected]:;t;Jt!.Wi~ll1*U.O:P'L..·if!fjM:ltltl:&!;Uff.lIl«I't.JWWa;t~~(jM.:fi)' it.f.tfMIfI&6f2jf:l:¥tO~P'lm~Ult~tti'bRUfJW/Jil

-f$M.fi'iA '

1f1I1'!;;W::?eEEJ!:p:M.~(fJli!nEl3calcineurin lQJ!lirJ~(CNl)~J;)fFif!t

• .flHffram.rn11ff[; ,

l"l[liflfN6fjMI'fJ\lifllilmj~ • ^#~~!it

H"J830U1W1J...~)mAR"trJ,,"/j>Ml:iIIil!I:.iiti$(slomerulor

liltrotion mle

: ^Gm)fl-~t£20-40 mL/min;zJH1&"/h~iIIM!.il!l$tE40

min/ mLl.:J.

J:~=m, fiif*~'gJ!:!ilif;mJ..EI3calcineurinjl:JlIiiJm"WJ;~fFi1IEl3t!lt1.fiJllJm:t&~1t'RJ;);f!l!:' Y.liiiJ..t!l!:J,:JfFms:ml~HltjJJl.MB~i'f]Jt

f1Iitl!'AliiiWi«:Jmm : lIt1i- ' tiJf'U ..

1JtIA8S'!a!<tl0:IkT(f]'R'd,:u.l!I~iH!$U5M40

mL/ miuil!! ' It5IW:rruw!k .

~t.l:li~.'F&t@

. tHGI'fJ'ilf1lil

ll1~m;!( m1I~~)llltlEL:'I'IlIllH'&I!!l'JJI(""i<ii<i

.

fl,1ffill!!~j;"'iltIi>""",)"8'JIl!"'IiIMIIO

lI.T-n&l'!!(M ) 1 •

.i!IJJ'iJII*!l~tle:tr':JJJ IF. J:t!j;)

WtJilljfi'l6(W R

~

1 20f]?! R

fI<j ,

H

j;)M·fi5MlfftiHtcalcineurinjq):l;Ilm~Je;/j :!3calcineurinf!lJ~l

mLlta

fF~1i!

I'fJl&\lff.~~ : 1N.A.f'HItl!mrjl'¥];U:fI!!~m:tQJ:tijm1!Ift!imyoopbenolate

mofctil(MMF) •

azathioprine(AZA)&Bi:'l'IlI1fillll!1~ • ffm81'f.J;t!l

It5J!f1JJtJ:-'$

12-201}lt.

'

st~~UiM'J!fII:ltJ;J.tUJJ1IJo:J:lsirolimus~Ut.iIllJttE8-20

ng/mL(J..1'§1If:»-mltfeilW)

·l:!1l!If'II(;!:;mftt~MlmutHl.r:&

mI2fWFf!l.'fI'fJJf/j,~jj~,*~. Jt(!Mljt'i!lM~tfitIJI;I]Jtrn.{fJf@:ttl':lf.Jl;.&:lIl· {i.M9<:J&;Q7EL:~· ~ill(jjiJl'f.J"!j'AAilt~Ja!*.w.lMl

40

mL/minIf.JWiAjlftli'ili~!lIlr:.f(FfIl*~ca1cineurintlll(jilll'fflrafRwtA.1'f246{ll' "'1'J~fFi1'!II~1R1l'J1fifJ...l'i497t:z)·

fll'lf1B!i=WIlIi

*litt3:1liJrnwflt '

J,:JNMlkivclln~i\:MW4A!¥Jf'f/JWlill~~$:M!i'1fljjj~{hwt~!U1!DM*

• • ft{1: • fNi£M:iE£i. Jf IJ

~i1Imljlf!$

>

40 rrtL/minl'fJ'N8ril~.f;1IfM J,.a1IJt~fFm!litHRrnmJfa

(1Il!ll<1M1i1!1i)

a\{tf5ftffmSi11~ 1:iU1H~5'tCalcincurin

mJJ!{iD"

JB.

!!II:

N=196

trJJiIi'j~mlB

(95%CI)

I ~f:t(tJ'i!f/j,J":j(i!f.l!!!.a!i!f.1

mL/min

(tJ.Nankivell1f.£il.A~~) 21f:~(f],*'J\~iltMi!l~$

mL/min

(.l.).Nankivell}j~~tPt!~)

:59.0

53.7

N=245

1.3 (-1.1,

3,7)

52.1 1.5 (-

1.4.4.6)

itlml4:&2~m:' ;1t~tI:*Xffmfi:

-

ntd'llft!l~~

- )tLJt$ffJ{I;!

· 'itl~WHDlI±VJUn::f.aEU!:(£JiLJ~~fFmllj'jiJ"'ffi!~i!i¥Jij~~il'1i· I)bik.®:::t=..${£i!II:li~}i'"iffjf~I!;08o:J:ltl(iI'Jj •

1'EIOOIOIMM ' iII=III,i!A"''''''llisllOlMlII11!1i!1ll!lti'8'J'l'''JIOll.<PtiIH!I!IJ;( ' ff!"' ''',lC&,lCli>, 1'EOIfjO<l"i1lllfll1"'8'J WiJ... :;;P;lA-iIUUflifi iii

Bfi nfttl fit8"JZP:~ftt.!& 'llfilJj/~I;tHM1(l';JHS:m~Mti~ca1cincurinl!llmrjmWltHnWiA

'

1fj':)i

T

~ (

.. M

1f~~&ttl!

m:lfl(5,9) J • JIt9}

, :frl?'if:ftm5'tcaicineurinf!lliMmlil~((-J~AfElltif£

'

Yl11i&f.\r:i'l'f1fitl~tr',JIi>iAtEltf:ffl:J!2tf:~IY,Jwnx~mBf'IOO

WTlII11!1· IIll!lt Ilitll!l!ll8'Jlil.\l\Jt il' 1Ill'1i<i

(T-;ro~OI<j!"'OI!iM8'J"'i<li'i'lli

a ilI"MlII11!1i!1L!1lt i_JO>i*;,lllt'J ,"

I) •

""iii"""

::'f,l:!lliil.!r&;;;:IWElfr~!JiIEl'iJft1mBW(ncphrotic

raDge proteinuria' :l:l!fijm<i!iJ:j:llliBif!JlUlIlMl'ffiJIl!l.ttfrt:l>3.5)tfJli'iA'

m.M~~fi:

i'I'llfm~WIIJ:l;a~m~calcineurinfflJ$IImraHfll!:~gm~'Rf±m

SW-( 46/482[9.5% 1

^vs9/239[

3.8%]) ,

ft~jjl:fAiXi'tl~JlfJ«·J/Jf1.i!ir:pm

BI!l!JiillIlmflfftmllJf:/iil> JU~ , ~irolimus;mD"ttliB,*{h1"JIa£f.\.!Ill:~(fi:i'I'!1InI3129

'

Calcincurinl!P%~"'Jnl/14)

• rg;f'j\Jjj(il4!:j®i'!$. > 40

mL/min{h~m~~:(£ii7ffljjijl$ljil\lij21f:1k1

'

~itl(t:f:im S 'N!iIflWtlfFMillm:1t

N

410

0,35 ± 0.76 0.13 207 0 .28 ± 0.61

0.11

423 373

O.I'!~,t;

1.61 0.86 ± 1.48

0,3

1 0.32

>OJ 190

0.37 ± 0.118

0.47 ± 0,98

0.14

0.13

p-value 0.381

<0, 00

1

<0.001

§1'I"iJf,'tJ*~.IE.~i¥Ji1I'f4m'~l.:J.fFiff.lti!:ftcalcineurinmHMJ!fIlflkm"tf~tlJEV:fDif$.fIt';[jf.4J...{f-]ijU''tmlli't.~:l€Nfl!lJm:i!:BfiOfAI'f.J'!!f1h

~, (E.IJlf'fI't.ll1f*lWlij';iiJll~e-i~fIi.IA~i{fq:.l'n~amiAa:J:ft,

;!tiNMIJltW ...

t!'J.tiflmftlfttMRf,l(rtJJJi~t'i'iOi :

t;',j)ltm::mmmm

Al'&alcincurintm"J~"HUlfFmilJr,j' te::Ilf..t.;l1lfjlJ~-{1UfiA!f!m"'~I'f.I3!jJ!:' ~~L(em~tw:tlil~E~UJJJlms~!l:I1:*t't.ljjiiJ...· 14.8. IJ\~.,1

fi:itf Wft-Jfii(;!:; '

JeJftffiffI4'W::It~Ii!l~O:P{."

:tl!fj- M£tKll36iWJi 'fmh!l:1t, r:JIlI: -

Rt:ltlJm(f.J~Jf.;Hil:M*IHI't!i

:

~ltt2t,*m, ~ iW~:fl:

R

~iili:ft:ttft

II!HJ

~R-~(r1i9i~m:.&uJ&-MIW.fj;fti1mif:

(3)'1)< 1 8, !it) •

rtt.~~ J.l!mW"H" .il!l-~ ( a ) J,:)J:~~ 1!I:J'UflfHI,{IJ~Jl: 1iif jf: ,

lOn£.1t;:'\!fliJJtJ:j:lllJJUili1:ti¥4I!nf$M'j!fffiij

0 78(i'l~II:M/fttt!!.t:).2:ll'fJltWIJ· m",Jm.ffl rRapamune+ealcineurinIIlHMI'III+~JUgjm (sirolimusZ§~!ln.O:Pi.llftHt!'i-I'

ng/mL'

:pfl.:J.~fi!l7}I1i~*jHfi' ~ti:53Ul.rrtlit)J ,!j.It~~HIJ,:) rcalcir.eurin/!ll;1;ll~ffl£i!!J tfJ~

£im~:i!1\!25ro:rf41it)

•

Wv(f];1itM~IO;li!mti~ru.:

' ltltllffl:ff!:1!EtJf:fF{WIUil!liIJtlHf") -

~tlt9<:/l!(~1EL:

•

Jtt~.~lilt

. JiH:t r.1;j",

r.'rff'tH+(calcincurinlfllll!~~~!tJll)I'fJ~&I:j$;J 'It r caicineurinl!P!!1JJ!\'Ilf.i~ir.HfJ~$J

:iJf:I.tK •

3!ifIHR*~HtI¥J1il8l!::k.:l&tt

$, :(£ff:mIfM-z,45.3% '

~:tfjMY.:t44.0%' R:M1&~IlI;T-::Itf.l~ ·

ffJiNWCP'

~-H-:t~:tit7EL· rfi:i1IlI+c

a\cineurinJjJ:tiiJJ'i1+M

~!t1

J ;t!:W

J;tjflgeft;~(('1fft1JUfojH

' iliJ:!IfIr.1ti::flE?;(

1!Lltim'f!!Rb:):IOJ.o::p:=.mrt:ti1l!!It1&lJIlOIm~l!tt1JJ)1itf"HiRlA~Wd'l!iiil!" R.-IfMf

.&t:tJl!:lfIlf.i(5.8

)] • m11NilitltMu,f.:x#i

r

fi;if'l.+(calcincurin.jQli!fiJ~m~i1!){f-]!€'Kf~i:1;J MLttm'F.ffiM~:iif:MilItf·

15

.":>1:11

Clinical Therapeut ics. Volume 22. Supplemcnt B, April 2000r $J'l1f!rt;/'R:it( 2)

1 • 16 §!IOl!!t!I/JIi'l¥"'~fF

£il~fi:II'I.-1'.@a::r9iJilll'~r&'

!!1Jlt::f@ill!Wjjl/r:t:ft'?&ffii '

tm9!P'I~~!!IJiCUlmMl&"~1MM~' &,~Ifl1E~&A<::ft:7:.jt!I~

: IF.!

~IlIHllJIIJmm*~Mt •

1T-i'A.tEJIDiI.a8mJt&7i·~..l:ffi&l,y,((J"ti~BWlz.*rrJo/J{t!m -

t*J1I!l1&'j!!IJzi'i%c.BMllflffltf!7f;f:lffil'nItl:M!:- x -

16, 1 ~)I:ii.l';llelfllf.l

'tv

-fl?1.Fj<i'f!fHf";]lJ!liilJ':lll(NDCNOOO8-\030-06)t2~Q:,*,~'ff -MP'i~2ft<ij(mnW)'i":oli",u~(iQBl~I£;,f.t;f~W.)il"[email protected]&:JlI1JUl'

rwllltJ'lilli1'EU8'JoiIiTt>!ftfl;jjlh";llS .

",~J"«'J(M>BIil"'IIl'JlIIllllJJ:liItlll(goml.o!"'t>g;fl;jIO"'l"

ll.-iI<ll" !I':; ·

1f!i!Hii'fJ'/1:"rt'iH0l1llt1il1flJ&-{IUliit'

!lkM'1ilrf2·C~8·C(36'F¥.46·F)(fJ.Illm· jfJi:-T---Hrm~' JI!~-fiilRt'1'

lI!f.,tI<0tt¥JJIMilAHM

· ~ :fH

I5:lll!·

ViAiiJ~.fBi:~II!i:l1HM(WIJ~'

f'l:X ' {B.:;;P;PJiiliMlI!'ix)U1l-r¥1'£25"C

(77"F)I¥rMnlJlttt·

JlJ!J8~tUtlli'i;ro~ "f:@:fn-f'l't8 ~~

m '

^{{-'f ./rl!{:t.}

^iUftm

^J"j

^i'f

^{1~~ tfl~}

.RllUt25"C

{TIP" )H''1¥.IS.&l.t;l~

{±2-C ¥:lfC (30-F.¥.4o·F

)

Il" J.IllJR:

mlfi.241j,~ • m*mmMt ' I'!:!fftt~r.f:'&-'· [email protected];"~

,

n!~sz:tlj~ffl •

JIii~rnfFi1'!If~lIIiiilI'tlJff,"M~~l ' IIIIm8.im~ttMIl1M:W·

UU*i!i1:.Mf4 I'fJJ,IHfllt;j' , nJJ!ffJl/.1::8!J!liI11$'i!:i/il

'.M!.l:U~e!l!Jt!!Ml~K!tf'-OO:

flJiif4lit'J9<:

• r"n{h!:fjm!lt1.::f~.il'l'ir¥bft.l~t1 •

16,2~~.m:

"iIf.~8'Jrn

..

w.~ll.i'lllim~~·

• NDC 0008-1041-10 ' 1i},M , Be= PJ!:t!!.ttftq

^,-Itii:tIJ~

rRAPAMUNE I mgJ * tl :

^IOOm.Redipak$1il~(IOtJ~j8ffi'"

,

^{1ilJ~IOt\l.)·}

ffi1f.tl'ftl1£,~a::(f.tc20·C~25"C!¥J.lf:IJfHL'SP

Controlled Room Temperature)(68"F.§::n·F")

· fil.!lI'llnit ' J,:l!tl'i!.eYti!i!W:U#J%Ufii'@~

(fJ:!@dl, • ~~£J.lJ~~IiS"I1l'\!I; -.n:Yt«-Jg~P<J(~USPtnZft) • 17 FF:)~.P:l1Hi'i'mjlflJB9fl!F§~OO

1.Imr.¥JElJllltm •

• mIHlillU:fI'·Jml1H.lli(~p~w:mf8

'

J;)'Im-'Ji:~fI1B1a:fJlm(iIlI)·

',1iI-"'Ii!III-IIJiIliIlllU~""'Ii!I'lIlli<li~rr

'

• Jlff[::JmHi!kf'iiHl1€i-i'.li:(-ft:m;-T!'fJ~lJ¥ff)'MW.tt!!fifiAlilipq,

fJti:f!HItHiliO)'!fZP:

·

• - a..jjj }'Jt-'

=-f!lillf:1tFtIfi 'rft!f::l

CJlJHt:!lffmW.g.*X(!lil2) • 3,

llI.;:lIDJIl" ilfll!

I'lg~ii>~1Il1!!

Ii! IllIIi8'JlIIllllJJ:JlI!lllte

]J

ffllt>i-jf]!j •

• ~Wt~AJJ.N:m{£DmIt£lM1ijrnfft~fN#I:(l!n~jl.i! •

• ~~lf&Olm.ttO<JffiJ~It!1!!MiAm€f~IYJ~O(1II3)· 4.M!.Q>::*nmlMlTI.I'fJ~if!fmP'lIlli(fl~~.

'

• :fIft>g;f]!j"8'Jffll1<I!.IIl!Il!t>!'lll1 •

[~3!fflil!l!i"'ffl!(fJ!!\IiIWtEg;15!L

I!lJill(fJIOHUt", •

• f&:JJlJfjMA'J9i£,WMIfiIT •

• ~:!;IH~.tf1fpql±lm~!tl

'

1l'f:l4t±.ifm0!(r')~,'iht:ttIDJf:liP'l

' lIfili/ittitHI:!f7M{3'&'4(!i!4) •

5. ~n

* ftm¥Jlfllffi 'l!

!,r,:lijtm

r.J.liM\''t!T:!:t i:I :

• t4r*!~£,~~e1t:.ti'Ufrr-~lfpqIlEi.RIi~fI'-Jt:Utf'iiH"1:£,!liAlIiji

,

aM~¢!ruJt!!lf!}~--Ti:itEtU'ilmJ: •

iti 'f ,e,i/I-Pti- §lII' U: (iII5) •

6_ :Iff

e.:ii~i.H~·rni:tMMl [Rn':H~1 ~mIlfJI¥J;Wmi!

P<J(!II/6)

• nRIII-mrFiIf.I'lni"'~

,

• l!1Ji:tH,tff6P:l'r1~,'ii',tl:A!M:B¥.Y.60!£Ho\hJcWZMmrt{fJJ&:fI4~~;ffo:p • /lIlf.!lltI:¥l'-B • . :ili'!.TI.wj~

!ft.

•

llJ)m.¥.Y

I201}:MH'-JJiI.!ilI:iWifll't.¥.::t1Jt1'fJ!i!ill:ms:@lliJ:j:l' PJ.:xM;.~lltf~' _U:TI.~l;~5i::. mW~J'f:if!j

1i!I'lIlli<limWlI.,tt . lilMilIDtt""1til!!iilillil<kU!1II • •

m"",!!!"fflll<l~'.I'

liIi"liJl!.OlJt1!f11lllt

,"""If •

•

t>~jl'll!",IH'i41l11("'ffl-t<

' ll!ffl1J>,e,i/I"'lI1(1iJ7) •

8.!fI;J<rmB."'f!lffI!K~I'f.J~o%~j@~M<ri'iP'l •

iFi'l'til:?iIl6l.ili':1'fI110i*:i}W: J:!ii!i:Ji : Paiheon. Inc.

.ttl! hl: 2

1

00 SynteK Court Mississauga,

On1~rio, C>.n,,(I~

L.'IN 7K 9

• j6j' ~ffijMHc.Wi(5:!ifII) 1I:IHJtfi~0lf]atl!tB-01'1]

1tf!

J]J:: fIj';!trtfl1t*WiQ'lE!t:!Ul-=j.jhnllt

fFi'I',mti: 10** :

IIHilltl1 : Wyeth Pharmaceuticals Company it!!:

./:.tf::

Slate Road No.3, KM

1

42.

1

Guayama,

Puerto

Rico 00784. U.S.A

0~-~~~:~~~~~ffi~~0~~~Ji

.It!!

:1:11:: ~tt,",WTftmso:pi~Ht,*'i(jj290~;;L.l

Jl& ~:

USPJ 20 11 07-1

17340116