`

   
` 
` !!
`"

#$%%&'%()
`
`*+ %(%'#'&%,- $(,.&%&%/
`%/0#'%'1&'2 $(,.&%
` .2'2#&(,&%,&%
`#'&%',1&'2

+#'
`'3$$&,#,
`)

  1 

`  *  4
`5  1

1 6  * 
`7
`8
`
`
` 
` *    
`   
`0 0
`
`9:;;<=>?@ABC@DEBC=FG@<ABH:
`IJ=<K<@LB?MMG;G?LGN@OBP;GBQG;;RB?@SBHNTU?@RABC@SG?@?UN;GKABCV
`WJ=<K<@LB?MMG;G?LGN@OBXR<LYB:R<=KLBHN=UEABZ[@LG@>SN@B\?;;<RABJ:
`]JY?=T?D<[LGD?;B^<K<?=DYBHN=UEABHY?=;<KLN@AB_H
``H=<F<BHN<[=ABab
`c^[KYBJ=<KdRL<=G?@B_LEBQ[e<fKBa<SGD?;BH<@L<=ABHYGD?>NABCQ
`gHN;N=?SNB_U=G@>KABHb
`hHN=@<?;BHN@K[;L?@LKBNMBHN;N=?SNABQGLL;<LN@ABHb
`
`*  
`
`i#%'&-$+($(,.&%j ,k(%(%'#'&%,+&%/'#'%'l&'2 ,'.0
`&(#.2'2#&(,&%,+l#,(('+- .#'&%',%+&%#
`2#,4
`'&(%'+0#,m+#%+&n+.##0/.,'+$- ,$+.,-'#'0
`%'-+#'',3+$$+&,#,)
`#'&%',(&3+!)!o ,!)o ,
`32&()&)+)-7%'2,p32&(0'#'+.#'&%','2%(,,+3'!)o ,)&)+)-
`7%'2,) ,(%(%'#'&%,l#,+,&%/#3#&+#'+ q

0

#,,#$ji#%'&0
`'#'&%&&'r!)%/qk).#'&%'(&3&%/!)!o ,2#+#%$i#%'&-&# ,&%'2
`
`+j%rs7,#.,k)'8- j)ok'/2+,#.,-'2!)o ,
`/.ll'2i#%'&'#'&%&&'- ,p%%t(++!)4%/q) ,l#,#,
`
`l'2&&'-i#%'&'#'&%&% !- !js)7ok-,&#.,'+,+,#.,(0
`('+- 7.#'&%',+&%/+,&%/&%'3#'l%%'2,s#%+ )22&/2,' #t
`#,+!)!%/q#'42,.,'+,((+&%#!)o ,0'#'+.#'&%')2,
`,',&%+&(#''2#'%/0',-'.&(# ,.2'2#&(,&%,#'+,,'2#'#
`(&%&(#$--&(#(&,-'#'&%/+$$l&%'(#,#%$,$,'0l&+--(',)
`
`   
`
`5#'(%u%('&3&'&,,&((#j5 k(2%&(+$$+&,#,&,#-,'#'&%/(%+&'&%(2##(0
`'&n+$,%,#'&%,-(#/&''&%,,%&%/.2'.2&##%++3&,&%),.&'#--('&%/
`
`vww
`
`TEVA - EXHIBIT 1021
`
`

`
`millions worldwide and substantially altering productivity and quality of life (1, 2), therapies for KCS
`&&%,l+l&+#%+,,'#%'&#$#'&%/.+('&3&'$#%+i#&'$-&-j k'2#.&,-5 
`have been palliative at best. Recent advances in understanding the pathophysiology of disease allow
`2#3%.#&#'&3#',') (%'#+3#%(,&%%+,'#%+&%/'2.#'2.2$,&/$-+&,#,#l
`the development of effective therapies for the first time.
`'2+3.%'---('&3'2#.&,-'2-&,''&)
`The ocular surface, lacrimal glands, and interconnecting nerves form a homeostatic functional
`2(#,-#(#(&#/#%+,#%+&%'(%%('&%/%3,-#2,'#'&(-%('&%#
`unit that maintains normal tear production. Chronic dry eye disease results from a T cell-mediated in-
`%&''2#'#&%'#&%,%#'#.+('&%) 2%&(+$$+&,#,,',-#(0+&#'+&%0
`flammatory process leading to a disruption of this nerve traffic. Multiple factors, including an age-
`-##'$.(,,#+&%/'#+&,.'&%-'2&,%3'#--&()

'&.-#(',&%(+&%/#%#/0
`related drop in systemic androgen levels and chronic ocular surface irritation, create an environment
`#'++.&%,$,'&(#%+/%3,#%+(2%&((#,-#(&&'#'&%(#'#%%3&%%'
`in which activated T cells are recruited to the ocular surface and lacrimal glands in a vicious cycle
`&%l2&(2#('&3#'+(,#(&'+''2(#,-#(#%+#(&#/#%+,&%#3&(&,($(
`of inflammation that ultimately results in destruction of the lacrimal glands (3). Cyclosporin A (CsA)
`-&%-##'&%'2#''&#'$,',&%+,'('&%-'2#(&#/#%+,j4k) $(,.&%j ,k
`topical ophthalmic emulsion targets the inflammatory basis of disease by acting as a local im-
`'.&(#.2'2#&(,&%'#/','2&%-##'$#,&,-+&,#,$#('&%/#,#(#&0
`munomodulator and anti-inflammatory agent. By inhibiting activation of infiltrating T cells on the
`%+#'#%+#%'&0&%-##'$#/%')*$&%2&&'&%/#('&3#'&%-&%-&'#'&%/(,%'2
`ocular surface and lacrimal glands, production of inflammatory cytokines is prevented (4). CsA treat-
`(#,-#(#%+#(&#/#%+,.+('&%-&%-##'$($'m&%,&,.3%'+j6k) ,'#'0
`ment has been shown to decrease several molecular markers of immune-based inflammation in con-
`%'2#,%,2l%'+(#,,3#(##m,-&%0#,+&%-##'&%&%(%0
`junctival biopsies of dry eye patients (5-7).
`u%('&3#&.,&,-+$$.#'&%',jx8k)
`Phase 2 and Phase 3 clinical trials have established both the safety and efficacy of topical CsA
`
`2#, #%+
`2#,4(&%&(#'&#,2#3,'#&,2+'2'2,#-'$#%+--&(#($-'.&(# ,
`at concentrations ranging from 0.05% to 0.4% (8, 9). CsA is currently approved for systemic treat-
`#'(%(%'#'&%,#%/&%/-!)!o'!)6ojsk) ,&,(%'$#..3+-,$,'&('#'0
`ment of immune-related disorders at much higher doses than those given for KCS. Oral administra-
`%'-&%0#'++&,+,#'(22&/2+,,'2#%'2,/&3%-5 ) ##+&%&,'#0
`tion for treatment of psoriasis or rheumatoid arthritis produces blood CsA concentrations in the range
`'&%-'#'%'-.,&#,&,2#'&+#'2&'&,.+(,+ ,(%(%'#'&%,&%'2#%/
`of 75 ng/mL (Cmin) to 655 ng/mL (Cmax) (10). Because it is a potent immunosuppressant when used
`-8%/qj &%k'7%/qj #tkj!k)*(#,&'&,#.'%'&%,..,,#%'l2%,+
`at these high doses, it is important to assess systemic exposure to CsA upon administration of the
`#''2,2&/2+,,&'&,&.'#%''#,,,,,$,'&(t.,' ,.%#+&%&,'#'&%-'2
`very low doses needed for treatment of KCS.
`3$l+,,%++-'#'%'-5 )
`Topical ophthalmic treatment with CsA requires 2600-fold lower dosage than does systemic us-
`.&(#.2'2#&('#'%'l&'2 ,i&, 7!!0-+l+,#/'2#%+,,$,'&(,0
`age (10). A preliminary study of topical ophthalmic CsA conducted during Phase 2 development found
`#/j!k).&&%#$,'+$-'.&(#.2'2#&( ,(%+('++&%/
`2#, +3.%'-%+
`that topical instillation produced negligible blood CsA concentrations, although sampling was sparse
`'2#''.&(#&%,'&#'&%.+(+%/&/&+ ,(%(%'#'&%,#'2/2,#.&%/l#,,.#,
`(8). The present study examines blood CsA concentrations of KCS patients participating in a much
`jk)2.,%','+$t#&%,+ ,(%(%'#'&%,-5 .#'&%',.#'&(&.#'&%/&%#(2
`larger Phase 3 study of CsA topical ophthalmic emulsions. We show conclusively that CsA is prac-
`#/
`2#,4,'+$- ,'.&(#.2'2#&(,&%,)1,2l(%(,&3$'2#' ,&,.#(0
`tically undetectable in the blood of patients treated with these ophthalmic preparations.
`'&(#$%+'('#&%'2+-.#'&%','#'+l&'2'2,.2'2#&(..##'&%,)
`
`PATIENTS AND METHODS
`
`

 
`
`Clinical Trial O e
`ie
`
` &%&(#&# 33&l
`
`Therapeutic blood monitoring was done at selected sites on a subset of patients enrolled in a
`2#.'&(+%&'&%/l#,+%#',('+,&',%#,,'-.#'&%',%+&%#
`Phase 3, multicenter, double-masked, randomized, parallel group study of cyclosporin A topical oph-
`
`2#,4'&(%'+0#,m+#%+&n+.##/.,'+$-($(,.&%'.&(#.20
`thalmic emulsions for the treatment of dry eye disease (9). Eligible study participants had moderate
`'2#&(,&%,-'2'#'%'-+$$+&,#,jsk)&/&,'+$.#'&(&.#%',2#++#'
`to severe dry eye disease as defined by 1) Schirmer test of Z 5 mm/5 min (without anesthesia) in at
`',3+$$+&,#,#,+-&%+$k(2&','-yq&%jl&'2'#%,'2,&#k&%#'
`least one eye; 2) sum of corneal and interpalpebral conjunctival staining of 2 +5 in the same eye in
`#,'%$p k,-(%##%+&%'.#.#(%u%('&3#,'#&%&%/-yz&%'2,#$&%
`which corneal staining was 2 +2; 3) indication of moderate to severe dry eye disease by the Ocular
`l2&(2(%#,'#&%&%/l#,yz p4k&%+&(#'&%-+#'',3+$$+&,#,$'2 (#
`Surface Disease Index (11) and Subjective Facial Expression Scale. Patients were excluded if they
`-#(&,#,%+tjk#%+u('&3#(&#t.,,&%(#)
`#'&%',lt(++&-'2$
`had end-stage lacrimal disease, punctal plugs, were using medications that could interfere with the
`2#+%+0,'#/#(&#+&,#,.%('#./,l,&%/+&(#'&%,'2#'(+&%'-l&'2'2
`study results, wore contact lenses during the study, or were pregnant or lactating. The study was con-
`,'+$,',l(%'#('%,,+&%/'2,'+$l./%#%'#('#'&%/)2,'+$l#,(%0
`ducted from July 1997 to January 1999 and was in compliance with Good Clinical Practices, inves-
`+('+-$ss8'#%#$sss#%+l#,&%(.&#%(l&'2 + &%&(#
`#('&(,&%3,0
`ti gational site Institutional Review Board Regulations, Sponsor and Investigator Obligations, Informed
`'&/#'&%#,&'%,'&''&%# 3&l*#+ /#'&%,.%,#%+%3,'&/#' &/#'&%,%-+
`Consent Regulations, and the Declaration of Helsinki.
` %,%' /#'&%,#%+'2(##'&%-,&%m&)
`After a 2-week run-in period with Refresh® artificial tears (Allergan, Inc., Irvine, CA), patients
`-'# 0lm%0&%.&+l&'2 -,2{ #'&-&(&#'#,j/#%%()3&% k.#'&%',
`were randomly assigned 0.05% CsA topical ophthalmic emulsion eyedrop b.i.d., 0.1% CsA b.i.d., or
`l#%+$#,,&/%+!)!o ,'.&(#.2'2#&(,&%$+.)&)+)!)o ,)&)+)
`vehicle for 6 months. The vehicle consisted of a sterile, non-preserved castor oil-in-water emulsion
`32&(-7%'2,)232&((%,&,'+-#,'&%%0.,3+(#,'&0&%0l#',&%
`that was identical to the 0.1% CsA preparation except for the presence of medication. Patients in-
`'2#'l#,&+%'&(#''2!)o ,..##'&%t(.'-'2.,%(-+&(#'&%)
`#'&%',&%0
`stilled one drop in each eye every morning and evening, no later than 8:00 p.m. the night before clin-
`,'&+%+.&%#(2$3$%&%/#%+3%&%/%#''2#%|!!.))'2%&/2'-(&%0
`ical visits. They could use Refresh® as needed through month 4, but no more than 8 times daily af-
`&(#3&,&',)2$(+, -,2{ #,%++'2/2%'26'%'2#%'&,+#&$#-0
`412
`vw}
`
`

`
`''2#')'%'27.#'&%',(&3&%/32&(l#,,&/%+'!)o ,)&)+)-#-'27
`%'2,)2,&%&'&#$.#(+&%'2!)!o#%+!)o ,'#'%'/.,(%'&%+'2&#,,&/%+
`'#'%',)#&,',,#.%,(('+#'#(2(&%&(#3&,&')
`'#+#&$+,,- ,l!)!8/q+#$j!)!o ,'#'%'/.k#%+!)6/q+#$
`j!)o ,/.k)
`
`*+#.&%/
`
`/2+,#.,l(('+&+&#'$-'2%&%/+,#'+#$!#%+%'2,
`#%+7)-&%#,#.l#,(('+#'#,&%/3&,&''2#'((+'l%%'2,s#%+ j(#+
`'2~%'2sx 3&,&'k)%+'i#%'&-$.#m ,(%(%'#'&%, 7.#'&%',#,.3&++,0
`&#+,#.,#' 467!#%+ 2,#-''2%&%/+,+&%/'2%'2s0
` 3&,&')+,#.,l-n%%'&,2&.%''/#%%()j3&% k-#%#$,&,)
`
`*+*&#%#$,&,
`
`3#&+#'+
` q'#%+#,,,.(',(.$#,,#$l#,,+'i#%'&-$+(%(%'#'&%,
`-($(,.&%)*&-$-+l#,#(&+&-&+l&'2!) -!) '2%t'#('+l&'2
`
`'2$0L0'$'2)2/#%&(.2#,l#,%'#&n+$#++&'&%- !)# 3#.0
`#'+(%,'&''+&%#l#'q#('%&'&0#,+&.2#,#%+&%u('+%'# )€!4
`.,&n 03,.2#,
` (%j5$,'%(&%'&-&(*-%'
`k) .%+,
`l/#+&%'0'+#'!) q&%#%++'('+,&%/#%
`'&.i#+.#,,,.('0
`'l&'2#'0&%,.#$,(j
`0(&t %(+ %'#& #%#+#k)

(##('&%%&0
`'&%/%2#%(+'2,%,&'&3&'$#%+,('&3&'$-'2&,#,,#$)
`'%#'+(,-'2#%#$'#%+
`&%'%#,'#%+#+l(&,&%#$+&,,(&#'+#%+.+('&%,#'qn6 l%&'+-'2
`#%#$'#%+&%'%#,'#%+#+)%+'2,(%+&'&%,($(,.&%#%+'2&%'%#,'#%+#+($0
`(,.&% '+l&'2'%'&%'&,-‚4)&%',)2l&&'-i#%'&'#'&%l#,!)
`%/q#'l2&(2(%(%'#'&%'2(--&(&%'-3#&#'&%#%++3&#'&%-%&%#(%(%'#'&%
`l#,ƒo)
`,&#.,'0+,+,#.,'2##%+'2+(%(%'#'&%0'&(3j !0 k
`l#,(#(#'+,&%/'2&%#'#.n&+#j k)&%(,'(%(%'#'&%,ll'2&&'
`
`…†‡ˆ‰Šw‹ ,-/2*+#., ('+- ,Œ#%'&'#'&%
`
`_?TU;<KBJ<=B=<?LT<@LBŽ=N[UBJ<=B\GKGL
`
`aN@LYB9
`
`aN@LYBc
`
`aN@LYB‘’9I
`
`:;;B\GKGLK
`
`
`4s
`8
`6
`
`!
` 7
`
`6
`
`(
`
`48
`6!
`47
`4
`
`4!
`4!
`46
`s6
`
`?RB
`“J=<KL[SR”
`6
`64
`64
`4#
`
`=<?LT<@L
`Ž=N[U
`
`2&(
`!)!o ,
`!)o ,
`'#'%'
`/.,|
`
`##.,l(('+- .#'&%',)l.#'&%',-'232&(/.#%+ -'2!)o ,
`/.#(2/#3 ,#.,)*#,&%l#,%'(('+-.#'&%')
`
`
`#'&%',#,,&/%+'32&(l#,,&/%+'!)o ,#'%'27)
`(%(+,.#'&%',l22#+(,,+3-'232&(/.#'%'27)
`
`vw„
`
`

`
`-i#%'&'#'&%#%..&&'' !0 l#,(#(#'+$#,,&%/#(%(%'#'&%i#''2
`&&'-i#%'&'#'&%#'#(2,#.&%/'&'2%t.,,&%/'2#% !0 #,l'2&,'20
`'&(#..&&'-) %/•2q),'#'&,'&(#(#(#'&%,l.-+%,&#.,'+,
`'/2+(%(%'#'&%,(#,,'+#'#ll'2&&'-i#%'&'#'&%)
`
`'+$
`#'&(&.#%',
`
` 
`
`*+l#,(('+-#,..#'&%- .#'&%','-6!%+&%#
`2#,4'&#
`-($(,.&%-'2'#'%'-+$$+&,#,$&+&%/#''#-6 '/2+,#.,
`3'2,'+$.&+j#k)
`#'&%',#%/+- 6'$#,-#/j%r k#%+8o
`j!!q kll%jsk)*#,&%(2##('&,'&(,-'2,..#'&%l,&&#''2,-'2
`#/,'+$..#'&%)2#'-(.'&%-'2,..#'&%j7o8q kl#,,&/2'$l
`'2#%'2,'+$..#'&%j88o78q88k''2#,%,-+&,(%'&%#'&%l,&&#&%'2
`..#'&%,#%+l.&#&$%%0'#'%'0#'+)
`
`/2*+ , %(%'#'&%,
`
` -s7,#.,-'2!)!o ,'#'%'/.%%(%'#&%+#%$i#%'&-&# ,)

#%
`'/2+ ,(%(%'#'&%,ll'2&&'-i#%'&'#'&%&%'2'#'%'/.,#'#
`'&.&%',&%(+&%/%'2s0 j# k)2%$,'+$,#.,#3'2&&'-i#%'&'#'&%
`l8,#.,-'2!)o ,'#'%'/..,%'&%/%$)oj8q k-'2,#.,
`(('+-'2&,/.)Œ#%'&-&#+ ,(%(%'#'&%,#%/+-!)!6%/q'!) ss
`%/q#%+(#-8+&--%'.#'&%',l22#+%3&,(%#&'&,l&'2,.(''#/
`,t'&.&%'#'l2&(2 ,l#,+'('+j#4k)&%+&3&+#.#'&%'2#+i#%'&-&# ,
`#''2#%%'&.&%')
`
`&#*+ , %(%'#'&%,&%/ %,&%/%'3#
`
`&#.,'0+,+,#.,j%r !,#.,kl(('+- 7.#'&%',+&%/'2
`2,-l&%/'2%&%/+,),l#,'2(#,l&'2'/2+#,%',%.#'&%'&%
`'2!)!o ,'#'%'/.2#+#%$i#%'&-&# ,) 3#sso-,#.,j !q !k+&+
`%'(%'#&%i#%'&-&# ,)24,#.,'2#'l#3'2&&'-i#%'&'#'&%(#-4
`
`…†‡ˆ‰Š}‹

#%/2*+ ,3,
`
`=<?LT<@LBŽ=N[U
`
`–;NNSBHK:BHN@D<@L=?LGN@B“@>—T;”
`
`2&(
`!)!o ,
`!)o ,
`
`?RB
`“J=<KL[SR”
`ƒ!)
`ƒ!)
`ƒ!)
`
`aN@LYB9
`
`aN@LYBc
`
`aN@LYB‘’9I
`
`ƒ!)
`ƒ!)
`ƒ!)
`
`ƒ!)
`ƒ!)
`ƒ!)
`
`
`ƒ!)#
`ƒ!)#
`
`#
`%(+,,#.,-.#'&%',&%'232&(/.l2(,,+3''2!)o ,/.)
`r '#..&(#)
`
`vwv
`
`

`
`…†‡ˆ‰Š„‹ Œ#%'&-&#/2 , %(%'#'&%,&%%+&3&+#
`#'&%',
`
`:><AB_<™
`
`=<?LT<@L
`Ž=N[U
`
`–;NNSBHK:BHN@D<@L=?LGN@B“@>—TQ”
`
`?RB
`“J=<KL[SR”
`*Œ
`*Œ
`*Œ
`*Œ
`*Œ
`*Œ
`*Œ
`
`aN@LYB9
`
`aN@LYBc
`
`aN@LYB‘’9I
`
`!)46
`!)!
`!)64
`*Œ
`*Œ
`*Œ
`*Œ
`
`*Œ
`
`*Œ
`!) ss
`!)66
`!) 
`*Œ
`
`*Œ
`
`*Œ
`*Œ
`*Œ
`*Œ
`!)!6
`
`7

`7
`76
`7
`
`
` 
`87

`
`!)o ,
`!)o ,
`!)o ,
`!)o ,
`!)o ,
`!)o ,
`32&(š !)o
`
` ,
`
`*Œr *l&&'-i#%'&'#'&%)
`r ,#.(('+)
`
`+&--%'.#'&%',&%'2!)o'#'%'/.) %-'2,.#'&%',2#+(&3+!)o ,-s0
` %'2,l2&'2'2 2#+(&3+32&(-7%'2,-&%/#,,&/%+''2!)o
`
` ,'#'%'/.4'7%'2,.&''2,#.&%/.&+) ,l#,#$+'('#&%'2,
`4,#.,l&'2 #t#%/&%/-!)! %/q'!)!%/q)2,3#,((+#$&%'2
` 02'&(,l&'2'#t#%/&%/-'42,j#6k)

#% #tl#,%'(#(#
`
`(#,,',#.,ll'2&&'-i#%'&'#'&%)*#,+%'2,,','2 !0 l#,
`,,'2#%) %/•2q&%'2'#'%'/.,)
`
`  
`
`$,'&(t.,' ,+&%/'#'%'l&'2 ,.2'2#&(,&%,&,#$+'('#
`3%l&'2#%t'$,%,&'&3#,,#$(#.#-#,&%/+ ,(%(%'#'&%,#,l#,!)
`%/q),'&m&%/,'-'2&,,'+$&,'2#'%.#'&%'(&3&%/!)!o ,2#+i#%'&-&# ,
`&%'2+#'#%$'&+&%/'2$#%/,'+$)
`2#, #%+
`2#,4(&%&(#'&#,2#3+%0
`,'#'+'2&,-#'&%- ,'(&%&(#$--('&3-'2'#'%'-+$$+&,#,)
`'2,3$-l.#'&%',l2+&+2#3i#%'&-&#+ ,&%'2.,%','+$(%(%0
`'#'&%,l%'2#% 0-+2&/2'2#%'2&&'-i#%'&'#'&%).#'&%'2#+i#%'&-&#
`
`+ ,#''2#%%'&.&%'-&'2'/2,&#.,'+,,#.&%/3%-.#0
`'&%','#'+.'$#+%,'#'&%/'2#'%/0',-'.&(#.2'2#&( ,,&%,
`.+(,&%,&/%&-&(#%',$,'&(t.,)2&,&,(%,&,'%'l&'2#%&#.2##(m&%'&(,'+&,'2#'
`2#3+%,'#'+#+$.%'#'&%-'.&(# ,&%'(#,-#('&,,,'&%&##,.0
`'&%&%''2+j4k)
`
`…†‡ˆ‰Šv‹ Œ#%'&-&#&#
`,'+,*+ , %(%'#'&%,&%%+&3&+#
`#'&%',
`
`:><AB_<™
`
`=<?LT<@LBŽ=N[U
`
`–;NNSBHT?™“@>—TQ”
`
`LT?™“Y=”
`
`s
`76
`!

`
`!)o ,
`2&(š !)o ,
`2&(š !)o ,
`
`!)!6
`!)!
`!)!
`
`
`
`4
`
`vw˜
`
`

`
`/2+ ,(%(%'#'&%,#,+&%'2&,,'+$,2+#,,,,+l&'2&%'2(%'t'
`-(%(%'#'&%,.+(+$#..3+'#'%',l2,,#-'$2#,%+%,'#'+)2#.0
`.3+#'#'%'.+(&%/'2l,',$,'&(t.,&,'2,-# { -'
`
` #'&% #.,,-'#'%'-2#'&+#'2&'&,#%+.,&#,&,j!k)#(.#,+
`(%(%'#'&%,.+(+$'.&(#'#'%'l&'2 ,,&%,''2,.+(+$,$,'&('#'0
`%'l&'2 { -' #'&% #.,,j!k) %#l&/2'0%#&n+#,&,#,,&%/#'$.&(#
`7!m/.#'&%''2(%++,'#'&%/+,- { &,!/q7!m/q+#$'#m%#,#+&3&++
`+,-8/q7!m/q+#$)2&,.+(,'/2+ ,(%(%'#'&%,j#%› ))k-86)s›
`67)8%/q#%+s7)6›48)8%/q#,.'+&% ,'+&,,#&n+&%'2#..3+#-
` { '#'%'-2#'&+#'2&'&,#%+.,&#,&,j!k)
`%(%'#,''#'2#.$'2($(,.&%+,&%,'&++&%/'.&(#'#'%'l&'2!)!o
`#%+!)o($(,.&%.2'2#&(,&%,&,!)!8/q+#$#%+!)6/q+#$,.('&3$j#
`
`k),,&%/#/#&%#'$.&(#7!m/.#'&%''2,+,,#!)!!!s/qm/q+#$#%+!)!s!/qm/q+#$)
`2,# 74!#%+4 !'&,l,.('&3$'2#%'2(%++,'#'&%/+,-
` {)

#%'/2+(%(%'#'&%,.+(+$'.&(#.2'2#&(,- ,,&%,
`#,,'2#%!)%/ql2&(2&,#'#,'8!'&,l'2#%#%'/23,,%l&'2,$,'&(
`'2#.'&(,)%#++&'&%.#m ,(%(%'#'&%,#37!!'&,l#%+'2##%+
`'2+(%(%'#'&%0'&(3&,3s!!0-+ll&'2'.&(# ,'#'%''2#%l&'2,$,0
`'&('#'%'j#k)2,,$,'&(t.,.+(+$'.&(#.2'2#&( ,&,,3#
`+,-#/%&'+l'2#%'2#'.+(+$(%'$#..3+'2#.&,'2#'#'2,3,
`(%,&++,#--%%0&-0'2#'%&%/(%+&'&%,)
` -&%+&%/'2#''.&(#$0#+&%&,'+ ,&,%'i#%'&-&#&%'2+-.#'&%',,&%/
`!)!o.2'2#&( ,#%+&,#$+'('#&%.#'&%',,&%/!)o ,&,(%,&,'%'l&'2'2
`t(%',$,'&(,#-'$.-&-'2,-#'&%,)%# 0lm
`2#, ,'+$-!)!o'!)6o
`
` ,.2'2#&(,&%,'2l%((%(,-(#&%-('&%,3/l'2,-&(0
`
`&#/#%&,,%l'2#%$(&%&(#$,&/%&-&(#%'(2#%/,&%3&,##(&'$#,,-&3
`#%+%#-%('&%jk)% (2#/32&(0(%'+
`2#,4,'+&,-!)!o#%+!)o ,
`.2'2#&(,&%,%$ -88.#'&%',+3.+(#&%-('&%,#%+'2,l&%'230
`2&(/.jsk)
`2,',-'2(%','+$(%,&++&%(%('l&'2+(%(%'#'&%,#,+&%
`'2
`2#, ,'+$jk#%++&%/ { '#'%'j!k&%+&(#''2#',$,'&(t.,'($0
`(,.&%+&%/.2'2#&('#'%'&,#$i#%'&-&##%+&,+,-#/%&'+l'2#%
`'2#'.+(+$#..3+,$,'&('#'%',).'#%'$ ,l#,%'i#%'&-&##'#&%'2
`
`+-.#'&%',,&%/!)!o.2'2#&( ,#-#'&%'2#'&,(&%&(#$--('&3-'2'#'0
`%'-+$$jsk)&%#$.2'2#&(..##'&%,- ,2#3#%t(%'(&%&(#,#-'$(+)
`
`…†‡ˆ‰Š˜‹ .#&,%-,#/,#%+*+ , %(%'#'&%, #,,.&(# ,2#.&,
`
`b=?;BHK:
`“VPb^:Q”#
`
`NUGD?;BHK:BbUYLY?;TGD
`PT[;KGN@K
`
`VPb^:Q—bUYLY?;TGD
`PT[;KGN@B^?LGN
`
`'#'&%/+,
`j/q7!m/q+#$k
`*+ #tj%/qk
`*+ #tj%/qk
` !0 j%/•2qk
`
`!
`
`7
`8
` 4 6
`
`
`
`!)!8j!)!o ,k
`!)6j!)o ,k!
`ƒ!)
`ƒ!)
`ƒ) (
`
` 74!j!)!o ,k
`
`4 !j!)o ,k!
`ž7!
`!ž86s
`žs6!
`
`##'#,(|j!kp,- { -'  #.,,-'#'%'-.,&#,&,)
`#'#,(|2&,,'+$)
`(*#,+%+(%(%'#'&%,-!)%/q'2/2'+,&%/&%'3#)
`
`vwœ
`
`

`
`2,,',&%+&(#''2#''#'%'l&'2'.&(# ,.2'2#&(,&%,-(#&%+0
`#'&%&,,#-#%+l&%'t'#%$,$,'0l&+--(',)
`
` 5 1


`
`2#'2,'2#%m) #'2%,#&'&,-+&'&##,,&,'#%(&%..##'&%-'2#%,(&.')
`,)#(2#.%/'% &,#%+#%/0&#.$,-/#%%().&&%#$
`.'-'2&,,#(2l#,.,%'+#''2#%%#'&%/-'2,,(&#'&%- ,#(2&%&,&%
`#%+ .2'2#/$j  k.&4!x

#$ !!!p')#++#)
`
`   
`
`) ,%)),)&,(# )'2l)#%+&,(2))%lm#'+$$+&,0
`#,#%+&','#'%'):SFEBY<=E8|6xs4 !!!)
`
` ) 5n# )

)&,(2))#%+1u(&m) )(%&(#%+i#&'$-&-&.#('-+$$
`,$.',)C@F<KLEBbUYLY?;TN;EB\GKEB_DGE6j6k|s  !!!),'#('%6s44)
`
`4)
`-/-+) )%)#%+'%

))2+&#/%,&,#%+#%#/%'-+$$|
`'l%'$0-&30$#3&l)HN=@<?EBs|766x76s !!!)
`
`6) '%

))*#% )1)t )) #) )

&(2--)5#%+
`-/-+) )2
`.#'2/$-+$$|2&%'#('&%'l%'2(#,-#(#%+#(&#/#%+,)HN=@<?)
`8|6xsss)
`
`) *&/%)
`&,#
`))#&%'#%

) +,(2&+

) /)#%+*#+&% )l
`($''&(#%#$,&,-&%-##'$#m,&%5 |70%'2'#'%'l&'2'.&(#($(,.&%
`)C@F<KLEBbUYLY?;TN;EB\GKEB_DGE6 |s!xs !!)
`
`7) 5%'5))&,+#))'%

))&'2))#%+ &.,%)5)%#$,&,-'.&(#($0
`(,.&%'#'%'-.#'&%',l&'2+$$,$%+):=DYEBbUYLY?;TN;E|6sx6s7 !!!)
`
`8) %5)
`-/-+) )&Ÿ)1))'%

))#%+ &,*))%'m&%0730
`,&%'2(%u%('&3#.&'2&-.#'&%',l&'2+$$+&,#,'#'+l&'2($(,.&%.20
`'2#&(,&%)HN=@<?Es|6s x6s7 !!!)
`
`) '3%,%)#) &,*))#%+'2 $(,.&%
`2#, '+$ .)--&(#($#%+
`,#-'$-($(,.&%.2'2#&(,&%&%'2'#'%'-+#'0'0,3+$$+&,0
`#,|+,0#%/&%/#%+&n+'&#)bUYLY?;TN;E!8|s78x0s86 !!!)
`
`s) #5)'3%,% ))

%+-) &,*))#%+'2 ,
`2#,4'+$ .)l
`'&(%'#%+&n+,'+&,-'2--&(#($#%+,#-'$-($(,.&%.2'2#&(,&%
`&%+#'',3+$$+&,#,)bUYLY?;TN;EB!8|74x74 !!!)
`
`!)
`2$,&(&#%, ,m -%()6'2+&'&%)

+&(#(%&(, .#%$

%'3# !!!)
`
`) (2&--#% )

) 2&,'&#%,%

))#(,% )&,(2))#%+ &,*)) &#&&'$#%+
`3#&+&'$-'2 (#-#(&,#,%+tEEB:=DYGFEBbUYLY?;TN;E|7x7  !!!)
`
`vw¡
`
`

`
`12. Gibaldi, M., and Perrier, D. Pharmacokinetics. 2nd ed. Marcel Dekker, Inc., New York, NY,
` ) &#+&

)#%+
`&)
`2##(m&%'&(,) %++)

#(mm%()lm
`1982.
`s )
`
`13. Acheampong, A,. Shackleton, M., Tang-Liu, D.S., Ding, S., Stern, M.E., and Decker, R. Dis-
`4) (2#.%/)2#(m'%

)#%/0&))&%/)'%

))#%+(m )&,0
`tribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and bea-
`'&'&%-($(,.&%&%(#'&,,,#-''.&(##+&%&,'#'&%'#&%#&',#%+#0
`gle dogs. Curr. Eye Res. 18291-103, 1999.
`/+/,)H[==EBPR<B^<KE|sx!4sss)
`
`Received: February 27, 2002
` (&3+|#$ 8 !!
`Accepted for Publication: March 27, 2002
`((.'+-
`&(#'&%|

#(2 8 !!
`
`Reprint Requests: Diane D-S Tang-Liu, Ph.D.
` .&%' i,',|&#%0#%/0&
`2))
`Allergan, Inc.
`/#%%()
`2525 Dupont Drive
`
`  .%'&3
`Irvine, CA 92715
`3&% s 8
`E-mail: tang-liu_diane@allergan.com
`0#&|'#%/0&¢+&#%£#/#%)(
`
`418
`vw¤