Intraocular Drug DelIvery - part 1 pps

Jaffe Duke University Durham, North Carolina, U.S.A.. Altaweel Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison Medical School, Madison, Wisconsin, U.S.A.

Drug DelIvery

edited by

Glenn J Jaffe

Duke University Durham, North Carolina, U.S.A.

Intraocular

Drug DelIvery

Published in 2006 by

Taylor & Francis Group

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New York, NY 10016

© 2006 by Taylor & Francis Group, LLC

No claim to original U.S Government works

Printed in the United States of America on acid-free paper

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International Standard Book Number-10: 0-8247-2860-2 (Hardcover)

International Standard Book Number-13: 978-0-8247-2860-1 (Hardcover)

Library of Congress Card Number 2005046669

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Library of Congress Cataloging-in-Publication Data

Intraocular drug delivery / edited by Glenn J Jaffe, Paul Ashton, Andrew Pearson.

p ; cm.

Includes bibliographical references and index.

ISBN-13: 978-0-8247-2860-1 (alk paper)

ISBN-10: 0-8247-2860-2 (alk paper)

1 Ocular pharmacology 2 Drug delivery systems 3 Therapeutics, Opthalmological I Jaffe, Glenn J

II Ashton, Paul, 1960- III Pearson, Andre,

1961-[DNLM: 1 Drug Delivery Systems 2 Drug Administration Routes 3 Eye Diseases drug therapy WB

Taylor & Francis Group

is the Academic Division of Informa plc.

DK3489_Discl.fm Page 1 Wednesday, January 11, 2006 1:14 PM

The development of drug treatments for diseases of the retina and back of the eye hasbeen slow Among the principal causes for this have been a failure of the pharma-ceutical industry to appreciate the potential size of the market these diseases repre-sent, a poor understanding of the disease processes themselves, and technicaldifficulty in delivering drugs to the back of the eye There have been recent rapidadvances in all three areas with many more changes likely to occur in the next decade.Until the 1990s, very few drugs had ever been developed specifically forophthalmology Virtually all drugs used in ophthalmology had initially been devel-oped for other applications and subsequently found to be useful in ophthalmology.One potential reason for this is economics In 2001 it was estimated that it took over

12 years and cost over $800 million to develop and commercialize a new drug (1).For a company to undertake such an investment there must be a reasonable expecta-tion that eventually sales of a new drug will, after allowing for development risk, atleast recoupe its development costs In 1996 the total world market for drugs forback-of-the-eye diseases was less than $500 million, providing little impetus todevelop drugs for these conditions

A major contributor to both the cost and the time it takes to develop a drug isthe regulatory approval process Following animal experiments, drugs enter limitedclinical trials that often involve very few patients These early studies, often calledPhase I or Phase I/II trials, are generally designed to get a preliminary indication

of safety and possibly efficacy while exposing as few subjects to the drug as possible.Once these studies have been successfully completed, a product can proceed tolarger, Phase II trials The goal of these larger trials, often involving 50 to 100 people,

is to generate sufficient efficacy data to adequately power the next, Phase III, studies

It is these studies, sometimes called pivotal trials, that are designed to provide cient data to satisfy the regulatory agencies that a product is both safe and effective.Data collected in Phase II is generally used to ensure pivotal studies are appropriatelydesigned and have sufficient statistical power to meet these objectives These largertrials involve hundreds to thousands of patients In clinical trials of an agent to treat

suffi-a previously untresuffi-ated disesuffi-ase it csuffi-an be difficult to decide on the primsuffi-ary clinicsuffi-al trisuffi-alendpoint to demonstrate drug efficacy This is particularly true for diseases that areslowly progressing, where a clinically significant progression of the disease can takeyears Any drug therapy designed to slow down the progression of such a disease islikely to require very long term clinical trials, increasing the time, the cost and the risk

of developing a drug Diseases in this group include diabetic retinopathy, neovascularand non-neovascular age-related macular degeneration, retinitis pigmentosa and

iii

others For a company developing a drug to treat these conditions, while risks fromcompetitors are always present, they become magnified in the face of very long-termand expensive clinical trials As a trial progresses, science advances and a competitormay develop a better drug or a more creative way through the regulatory system.The difficulty of the Food and Drug Administration’s (FDA’s) task in approv-ing drugs, especially for previously untreated diseases, should not be underestimated.Considerable pressure is exerted on the FDA to both approve drugs quickly and toensure drugs meet the appropriate standards of safety and efficacy The FDA is in adifficult position If after approval significant side effects are encountered, the FDA

is likely deemed to be at fault On the other hand, if a drug is not approved quickly,the FDA is likely deemed to be at fault The voices decrying the ‘‘glacial’’ pace ofdrug approval are often the same ones decrying the ‘‘cavalier attitude’’ of theFDA should a drug be withdrawn Despite these pressures, the FDA can move extre-mely quickly to approve new drug treatments Although it takes an average of 12years for a drug to be developed, Vitrasert1, a sustained release delivery device

to treat AIDS associated cytomegalovirus retinitis, progressed from in vitro tests

to FDA approval in eight years The total development time for Rertisert1, whichrecently became the first drug treatment approved for uveitis, was seven years Both

of these products were supported initially by grants from the National Eye Instituteand without such support, the industry has rarely funded the development of suchhigh-risk programs For major pharmaceutical companies the risks of developingdrugs for well understood diseases are high enough Add to these risks an unknownmarket size, unfamiliar regulatory approval process, new drug delivery requirementsand novel pharmacological drug targets, and the process becomes truly daunting

‘‘Big Pharma’’ has not perceived the opthalmic marketplace as large enough to port a fully-fledged development effort Pharmaceutical development has insteadbeen largely limited to smaller, so-called ‘‘specialty’’ pharmaceutical companies

sup-A turning point in ophthalmology came with the approval of Latanaprost, aprostaglandin analogue This molecule was developed specifically for glaucoma andhas been commercially extremely successful, generating over $1 billion per year insales in 2003 (2) This appears to have triggered the realization that ophthalmologyhas the potential to support billion dollar products and has lead to an increased focus

on the area by the pharmaceutical industry

In recent years there has been a dramatic increase in the understanding of thepathologies of ocular diseases and, perhaps not coincidentally, many new therapeu-tic candidates and pharmacological treatments Unlike such mature fields as hyper-tension, there is as yet no clear consensus of the pharmacological targets best hit togenerate an optimal therapeutic response Not only are there now a large number ofdrugs under development but there are also a large number of different classes ofdrugs in development Into the mix of increased commercial focus and rapidlyadvancing biology there is also the rapidly evolving field of drug delivery for the pos-terior segment of the eye This state of high flux is exemplified by the three treat-ments for wet age-related macular degeneration that are either approved orawaiting approval The first approved, Visudyne1, is an intravenous injectionfollowed by an ocular laser to activate the drug in the eye In 2005 it was followed

by Macugen1, a vascular endothelial growth factor (VEGF) inhibitor, given byintravitreal injections every six weeks RetaaneTM is pending approval and is anangiostatic steroid given as a peri-ocular injection every six months All three ofthese treatments have completely different modes of action and completely differentmeans of administration

iv Preface

This book is a snap shot in time In it the contributors have attempted todescribe some of the parameters influencing drug delivery and some of the attemptsmade, with varying degrees of success, to achieve therapeutic drug concentrations inthe posterior of the eye Also described are disease states of the back of the eye, some

of which, like wet age-related macular degeneration, affect many people Followingthe approval of Visudyne and Macugen, one could expect rapid changes in clinicalmanagement of these diseases Other conditions, like retinitis pigmentosa, are veryslowly progressing (making the design of clinical trials extremely difficult) or elseaffect only a small number of people, such as proliferative vitreoretinopathy (PVR).For these conditions there is as yet no precedent with the FDA for what constitutes

an approvable drug Progress in the management of such conditions is unfortunatelylikely to be much slower

Glenn J JaffePaul Ashton

P Andrew PearsonREFERENCES

1 DiMasi JA, Hansen RW, Grabowski HG The price of innovation New estimates of drugdevelopment costs J Health Econ 2003; 22:151–185

2 Form 10-K SEC Pfizer Annual Report Year End December 31, 2003

Preface v

Basic Principles of Drug Delivery 1

Drug Delivery to the Posterior Segment of the Eye 8

Posterior Delivery in Disease States 14

Future Opportunities and Challenges 19

References 19

2 Blood–Retinal Barrier 27 David A Antonetti, Thomas W Gardner, and Alistair J Barber

Introduction 27

Function of the Blood–Retinal Barrier 27

Formation of the Blood–Neural Barrier 28

Ocular Disease and Loss of the Blood–Retinal Barrier 29 Molecular Architecture of the Blood–Retinal Barrier 30

Neurotrophins Support the Development and Maintenance

of Retinal Ganglion Cells 46

Neurotrophins Support the Development of Inner Retinal

Circuitry 47

Models of Photoreceptor Degeneration and Strategies

for Their Treatment 47

Neurotrophin Delivery to CNS Tissue 48

PART II: SPECIFIC DELIVERY SYSTEMS

5 Antiangiogenic Agents: Intravitreal Injection 71 Sophie J Bakri and Peter K Kaiser

7 Pharmacologic Retinal Reattachment with INS37217 (Denufosol

Tetrasodium), a Nucleotide P2Y2 Receptor Agonist 97 Ward M Peterson

Description of Drug Delivery System 97

Spectrum of Diseases 97

Mechanism of Action 99

Animal Models of Disease Used 100

Results of Animal Model Studies 101

Drug Delivery and Distribution 105

Clinical Study 107

Future Horizons 108

References 109

viii Contents

8 Cell-Based Delivery Systems: Development of Encapsulated Cell

Technology for Ophthalmic Applications 111 Weng Tao, Rong Wen, Alan Laties, and Gustavo D Aguirre

Description of Encapsulated Cell Technology 111

Spectrum of Diseases for Which This Delivery System

Might Be Appropriate 116

Animal Models Used to Investigate the Applicability

of this Delivery System for the Diseases Mentioned 118 Pharmacokinetic and Pharmacodynamic Studies

Using the Delivery System 120

Results of Animal Model Studies 120

Techniques for Implanting or Placing the Implant in

Future Horizons 126

References 126

9 Photodynamic Therapy 129 Ivana K Kim and Joan W Miller

Introduction 143

Methodology of Laser-Targeted Drug Delivery 144

Potential Therapeutic Applications of LTD 147

Description of Drug Delivery System 157

Spectrum of Diseases for Which This Delivery System

Might Be Appropriate 160

Animal Models Used to Investigate the Applicability of This

Delivery System for the Diseases Mentioned Above 162 Pharmacokinetic Studies Using the Delivery System 163 Results of Animal Model Studies 163

Contents ix

Techniques for Implanting or Placing the Implant

in Humans (If Done) 167

Future Horizons 168

References 169

12 Biodegradable Systems 175 Hideya Kimura and Yuichiro Ogura

Fundamentals of Biodegradable Polymeric Devices 175

Spectrum of Diseases for Which Biodegradable Systems

Animal Models Used to Test Biodegradable Drug

Delivery Systems 180

Results of Efficacy Studies 181

In Vitro Studies of Scleral Permeability 194

In Vivo Studies of Scleral Permeability 196

Future Directions 198

References 199

14 Nondegradable Intraocular Sustained-Release Drug

Delivery Devices 203 Mark T Cahill and Glenn J Jaffe

Implanted Nondegradable Sustained-Release Devices 203 Implanted Microdialysis Probes as Sustained-Release

Drug Delivery Systems 216

Microelectromechanical Systems Drug Delivery Devices 219 References 222

PART III: LOCAL DRUG DELIVERY APPROACH TO SPECIFIC CLINICAL DISEASES

15 Photodynamic Therapy in Human Clinical Studies: Age-Related

Macular Degeneration 227 Ivana K Kim and Joan W Miller

Introduction 227

Phase I/II Design and Methodology 227

Phase I/II Results 231

x Contents

Conclusions 244

References 245

16 Age-Related Macular Degeneration Drug Delivery 249 Kourous A Rezaei, Sophie J Bakri, and Peter K Kaiser

Clinical Trials of Drug Delivery Devices for the Treatment of

Retinal Detachment/Proliferative Vitreoretinopathy 279 Systemic 282

Local Delivery 283

Direct Injection—Subconjunctival or Intravitreal 283

Sustained Delivery and Co-Drugs 286

Protein Kinase C Inhibition 296

Other Treatments 309

References 320

21 Cytomegalovirus Retinitis 325 Caroline R Baumal

Introduction 325

Virology and Epidemiology of CMV Infection 325

Clinical Features of CMV Retinitis 328

Diagnosis of CMV Retinitis 330

Treatment of CMV Retinitis 330

Local Modes of Intraocular Drug Delivery 333

Intravitreal Drug Injection 334

The Ganciclovir Intraocular Implant 335

Indications for the Ganciclovir Implant 339

Replacement of the Ganciclovir Implant 340

Complications of the Ganciclovir Implant 341

References 343

22 Endophthalmitis 349 Travis A Meredith

Gustavo D Aguirre James A Baker Institute for Animal Health, College ofVeterinary Medicine, Cornell University, Ithaca, New York, U.S.A

Michael M Altaweel Department of Ophthalmology and Visual Sciences,

University of Wisconsin-Madison Medical School, Madison, Wisconsin, U.S.A.Jayakrishna Ambati Department of Ophthalmology and Visual Sciences andPhysiology, University of Kentucky, Lexington, Kentucky, U.S.A

David A Antonetti Departments of Cellular and Molecular Physiology andOphthalmology, Penn State College of Medicine, Hershey, Pennsylvania, U.S.A.Paul Ashton Control Delivery Systems, Watertown, Massachusetts, U.S.A.Sanjay Asrani Duke University Eye Center, Durham, North Carolina, U.S.A.Sophie J Bakri The Cole Eye Institute, Cleveland Clinic Foundation, Cleveland,Ohio, U.S.A

Alistair J Barber Department of Ophthalmology, Penn State College of Medicine,Hershey, Pennsylvania, U.S.A

Caroline R Baumal Department of Ophthalmology, Vitreoretinal Service,

New England Eye Center, Tufts University School of Medicine, Boston,

University, Baltimore, Maryland, U.S.A

xiii

Lewis J Gryziewicz Regulatory Affairs, Allergan, Irvine, California, U.S.A.Michael S Ip Department of Ophthalmology and Visual Sciences, University ofWisconsin-Madison Medical School, Madison, Wisconsin, U.S.A.

Glenn J Jaffe Duke University Eye Center, Durham, North Carolina, U.S.A.Peter K Kaiser The Cole Eye Institute, Cleveland Clinic Foundation, Cleveland,Ohio, U.S.A

Ivana K Kim Department of Ophthalmology, Harvard Medical School,

Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A

Hideya Kimura Nagata Eye Clinic, Nara, Japan

Alan Laties Department of Ophthalmology, University of Pennsylvania School

of Medicine, Philadelphia, Pennsylvania, U.S.A

Albert M Maguire F.M Kirby Center for Molecular Ophthalmology, Scheie EyeInstitute, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A

Melissa J Mahoney Departments of Ophthalmology and Neurobiology, DukeUniversity Medical Center, Durham, North Carolina, U.S.A

Travis A Meredith Department of Ophthalmology, University of North Carolina,Chapel Hill, North Carolina, U.S.A

Joan W Miller Department of Ophthalmology, Harvard Medical School,Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A

Yuichiro Ogura Ophthalmology and Visual Science, Nagoya City UniversityGraduate School of Medical Science, Nagoya, Aichi, Japan

P Andrew Pearson Department of Ophthalmology and Visual Science,

Kentucky Clinic, Lexington, Kentucky, U.S.A

Ward M Peterson Department of Biology, Inspire Pharmaceuticals, Durham,North Carolina, U.S.A

Stephen J Phillips Duke University Eye Center, Durham, North Carolina, U.S.A.Zeshan A Rana Department of Ophthalmology and Visual Science,

Kentucky Clinic, Lexington, Kentucky, U.S.A

Kourous A Rezaei Department of Ophthalmology, Rush University MedicalCenter, University of Chicago, Chicago, Illinois, U.S.A

Dennis W Rickman Departments of Ophthalmology and Neurobiology, DukeUniversity Medical Center, Durham, North Carolina, U.S.A

xiv Contributors

Weng Tao Neurotech USA, Lincoln, Rhode Island, U.S.A.

Rong Wen Department of Ophthalmology, University of Pennsylvania School ofMedicine, Philadelphia, Pennsylvania, U.S.A

Scott M Whitcup Research and Development, Allergan, Irvine and Department ofOphthalmology, Jules Stein Eye Institute, David Geffen School of Medicine atUCLA, Los Angeles, California, U.S.A

Ran Zeimer Wilmer Ophthalmological Institute, Johns Hopkins University,Baltimore, Maryland, U.S.A

Contributors xv