LACRIMAL GLAND
`TEAR FILM AND
`DRY EYE SYNDROMES
`
`Basic Science and Clinical Relevance
`
`Edited by
`
`David
`Darlene
`
`Sullivan
`
`Dartt
`
`he Schepens Eye esearch Institute and
`Hai yard Medical School
`
`Bocton MassachuscUs
`
`and
`
`Michele
`
`Meneray
`
`ou san Stt
`New Orica is Louisiana
`
`Medical Center
`
`PLENUM DRESS
`
`NEW YORK AND LONDON
`
`FAMY CARE - EXHIBIT 1008-0001
`
`

`
`brary of Congress Cataloging lnPubiicat1on
`
`Data
`
`basic mc ene
`_acrimal clard tear
`file and dry CfC syndromes
`din cal
`Sullivan Da
`edited by Oavd
`lere
`Dartt
`releva
`Ce
`Meneray
`and Michele
`Advances
`cm
`
`med dire and bioogy
`
`in exoerlilenta
`
`438
`the
`the Second
`International Conference on
`Proceeci
`pm of
`and üy Eye Syndromes held Novenioe
`Lacrimal Glerci Tear bile
`the Southhaepton Princess Pesort Bermuda
`1619 1996 at
`versa
`ncftces biblicgraphical
`ISBN 0-306 45812
`Lacriiral apparatusPhysooqy
`-Congresses
`Dry eye sndommsCongresSes
`Corgressos
`II Dartt Dsrlene
`III
`lee icray nlichCle
`IV International
`Conference on the Lacrirnal Gland Tear
`lii
`2nd
`996
`SojthamptOr Bersuca
`Islands
`Cry Eye Syndromes
`Series
`
`references and
`
`index
`
`Tears
`Dull van David
`
`and
`
`congresses
`Lacrimal Apparatus
`congresses
`Dry Eye Syndoiies
`
`fearsphysiology
`1-41 AdbbO
`138
`
`9817987
`-P
`
`corgresses
`19981
`QP18S.T4L332
`612.8 47
`dc2
`DNLMD
`Cor
`
`1998
`
`ibrary of Congress
`
`Proceedings of the Second International Conference on the Lacrimal Gland Tear Film and Dry Eye
`the Southampton Princess Resort Bermuda
`held November 16
`19 1996 at
`Syndromes
`
`ISBN
`
`306-45812-8
`
`1998 Plenum Press New York
`Division of Plenum Publishing Corporation
`233 Spring Sti eel New Yok NY 10013
`http Iwwms plenum.eom
`
`109
`
`76
`
`43
`
`All rights reserved
`
`stem or transmitted in any form or by any
`No part of this book may be reproduced
`stored in
`means electronic mechanical photocopying microfilming recording or otherwisu without written
`the Publsher
`pe missio fm
`
`etrieval
`
`Printed in thu United States of America
`
`FAMY CARE - EXHIBIT 1008-0002
`
`

`
`144
`
`CYCLOSPORINE DISTRIBU HON IN1O THE
`CONJUNCTIVA CORNEA LACRIMAL GLAND
`AND SYSTEMIC BLOOD FOLLOWING
`TOPICAL DOSING OF CYCLOSPORINE TO
`RABBIT DOG AND HUMAN EYES
`
`Andrew Acheamp ing Martla Shackle on
`and Diane rangLiu
`
`eve am Ptr ck Rudewicz
`
`AHergan
`Irvme Californ
`
`IN IRODUCTION
`
`that
`
`ated
`
`im
`inhibits T4ymphocytemed
`is an immune modulator
`yclosporine
`munoreactiity Allergan is currently evaluating the clinical efficacy of 0M5o 0.4
`cy
`emulsion for the treatment of immunoinflamrnatory eye diseases such as
`closponne
`sicca or dry eye syndiome Topical ocular application of cyclospor
`formulated as 2% cclosporine in olive oil 0.2% cyclosporine in om oil ointment
`2% cyclosporine emulsion Allergan was found to reduce ocular
`ScheringPlough
`or
`dogs ith KC
`surfae inflammation and mproe larirna gland seertion
`esearch was to determine the ocular tissue distribu ion of cy
`The aim of the present
`in rabbts dogs and
`closporine in rabbits and dogs and to compare tissue concentrations
`humans after topical administration Determination of relationships between the ocular
`is
`for optimizing delivery of plarma
`and efficacy is important
`sue drug concentrations
`in the target ocular surface tissues providing support
`cologically active concentrations
`to
`the local mechanism of actior and optimizing dosing regimen
`
`keratoconjunctivatis
`
`inc
`
`METHODS
`
`2.1 Animal Studies
`.3Hcyclosporin.A was prepared by Amersham UK with radiochemica
`than 98% Female New Zealand white rabbits
`single 50
`kg reeei ed
`
`purity greater
`
`Lacrimal Gland lear Ithn and Thy Lye Syndronws
`edited by Su1Iian ci cii Pknum Press New York 998
`
`loot
`
`FAMY CARE - EXHIBIT 1008-0003
`
`

`
`1002
`
`chearnpong
`
`ía
`
`cul
`
`ular
`
`ssuc
`
`cii
`
`cc ed
`
`in
`
`3H cy losporinc form là ion -1 ir Ciml into the lower corjunct
`al dose of
`de sac of the left eve Male beagle thgs
`13kg ece ved
`35 lii dos of 02/o 3Hcy-
`mC ml
`cuLd sac twice daih for
`wer cor unc
`ospori ie eriuls or
`dec ed me porn
`ood were
`and syst uric
`over
`days
`96h
`ne pm
`The rahb
`stdose iT
`dogs or four rabb
`re used
`cx
`iod
`ted ic ordn to USDk an Al ergan kC
`iments were condi
`gu delrn
`le dog
`stud was ondu ted
`ity eoncn
`Life Scenrc
`ste radioc
`Hunfnglor
`Is
`prcsscd as ng equivalents eq of cyci wpo
`were
`is ue
`of th dose lormulatiot
`
`ie
`
`ci gram of
`
`ti
`
`ing ftc spe
`
`ic act
`
`22 Humai Range-H iding Study
`
`two mar sub cc with KCS ieceie1 an cyed op of ye
`or 04% cclo pot ne emu ior twice daily for 12
`ks Blood sari
`nd 12 weeks of
`en Iccted
`all subjects at morning tro ghs after
`blood amples we
`sel ctcd sr bjects at
`collected
`the last dose at week 12 Cyclosporin sA concentra ions in blood samples were
`c1ro latograply- arderr mass peetriimetry LCMS\IS
`the internal star dard The lower limit of quantitat on of the
`
`hundred
`
`5o
`nics wc
`
`from
`
`add in
`
`neasured by
`validated liqu
`method with Cyclosporin
`blood assay was
`ng ni
`
`and
`
`aLe
`
`RESUI TS AND DISCUSSION
`
`and
`
`Figs
`
`ibital
`
`clospor
`
`found
`
`in tears ocular surlace
`the time course of cyclospori
`ssues
`depict
`2% 1H-cy-
`lacrimal gland of rabbits and dogs after eyedrop instillation of
`1000 ng/g we
`ie emulsion Significant cyclosporine eonentrations
`for Cs
`the eonjunctlva and cornea the target
`redu lio of ocular surface
`tissu
`The 0.2% eniulso provided approximately
`fold higher eyelospo inc
`inflamniatio
`2% cyclosporine in
`in the rabbit cornea and orjunenva than th we for
`concentrations
`thaL of bood
`pine asto- oiL4 The lacrnia1 wand C11a was scvcral-fo
`ThpC
`emily in the dog
`The ocular absorption and disposit on of yclospor ne in abbits and dogs vere ciT an
`absorption into ocular and extraocular tissues reservoir effe
`acter red by rap
`the
`cornea relatis ely low intraocular
`tissue con
`itrations aid
`long terminal elimination
`half-life of 2044
`in most ocu at tissues Figs
`milar ocular distribution cfar
`and
`tudies
`acterist es were noted in preiious rabbit and human
`shows less than 0.2 ng in mod conce itrations in hum ans following mnulta
`Table
`2% and 0.4% cy lospor ne ophthalm ernulston
`stillation of 05%
`pie top cil
`The systemic blood CcA oncentrat ens in
`12-week period of dosing
`over
`imans afTer
`topica CsA doses of the cmulsio IS were much lower tha
`the blood trough concentrations
`of 20 100 ng/i
`il used or monitoring the safety of patients receiving systemic eyelospoi
`inc if erapy
`
`iig-cq
`
`CONCLUSIONS
`
`opicaily applied eyelosponne emulsion can produce significant concentrations
`in
`local immunomodulatory effect Tte ocular distnibu
`the cornea and conjunctia to exert
`
`FAMY CARE - EXHIBIT 1008-0004
`
`

`
`Cyc1oporrne tstributon into the Conjuactiva
`
`1003
`
`bJ
`
`ci
`
`ci
`
`ci
`
`ci
`
`tear
`
`coni
`come
`sciera
`
`laCiiflhil
`hlood
`
`A-
`
`10000
`
`1000
`
`10
`
`0.1
`
`40
`60
`Time hour
`
`80
`
`100
`
`Figure
`
`Total radioactivity concentrations mean
`
`SEM rabbit eyes ard systemic blood
`
`Sckra
`
`Lt
`
`iI
`
`TT
`
`1000000
`
`100
`
`10
`
`0.1
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Figure
`
`Total
`
`radioacnvity concentranons mean values in dog eyes and systemic blood
`
`Time hour
`
`FAMY CARE - EXHIBIT 1008-0005
`
`

`
`1004
`
`Acheampong et aL
`
`Table
`
`Human blood trough and maximum
`over 12 weeks
`
`concentrations
`
`cyclosporin
`
`yclosporme
`emu1son
`
`005
`
`O2/
`O4%
`
`Range of blood cyclosporine
`grnl
`
`concentration
`
`trough lesel
`
`Maximum level
`
`to 0.102
`OltoOlO8
`01 toO 157
`
`011o0144
`01 toO 158
`
`on of cyclosporine after topical application of CsA emulsion
`as generally aim lar
`rabbt and dog In the rabbits dosed with 02/a emulsion the cax tissue distribution was
`cornea conJunctia lacrimal glard
`blood
`tears
`follorsing topical app cation of cy
`Systemic blood cyclosporine concentrations
`closporine emulsion were very low in rabbits dogs and humans obviating concerns about
`con
`stemic mechanism of action The human blood cvclosporm
`systemic toxicity or
`ssere less thai 02 ng ml much lower than the blood trough concentrations
`of
`centrations
`20100 ngiml used for monitoring the safety of patients receiving systemic cyclosporine
`herapy
`
`ArchOpl-thalmol
`
`marketed
`
`by Scherir
`
`for human kcratoconjunetivus sicca
`useful model
`19 9107 210 21
`fa ireatmcnt of kcratoconjunctivit
`
`Ploug
`
`Kasan
`Spontaneous canine keratoconjunctivitis
`Ircare tw tcyc1ospornecycdroçs
`2% cyclosporme ointricnt
`Thc
`ca in dcgs
`Ghosn CR Fhc cifects of topical cyclosporine
`cii Mb elbcr 1A Gao
`KCS ARVOAbsuacts
`fri Set 19963
`.S10
`JiiestOpfthcdrnol
`TangLiu
`Shackleton
`\ngclov
`Acheairpong
`Lair
`ram ar aoueous emu sior Co wanson to other eyed op torm ii
`199637SlO26
`aol us
`
`tCsA on dry eye dogs
`
`ng Ocular bsorptioi ofeyclosponne
`ions AR\O Abtracts macsr Ophtha/
`
`\iede halt
`
`Kossendrup
`
`Pharma oknetics of topi al cyc
`
`porin
`
`in the rabbi
`
`Hoffman
`Shulz
`S/A 986 519 524
`eye Icr
`Op/it/ia
`Ksswan
`ti
`topically plied
`RE mt aocu ar pen
`2/ 65065S
`Ben Fira
`
`of
`
`ourt ii
`
`Tirnt
`
`er
`
`Ocula en
`
`asp iire Ttcrp
`
`it
`
`oc 198520 Suppi
`
`ation of eye osporir
`
`II The human eyc
`
`Br Op itS
`
`of
`
`352
`
`St
`
`/0
`
`FAMY CARE - EXHIBIT 1008-0006