Drug delivery to posterior intraocular tissues: third Annual ARVO/Pfizer Ophthalmics Research Institute Conference.

The third Annual ARVO/Pfizer Ophthalmic Research Institute Conference was held Friday and Saturday, May 4 and 5, 2007 at the Fort Lauderdale Grande Hotel and Yacht Club, Fort Lauderdale, Florida. The conference, funded by the ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics, provided an opportunity to gather experts from within and outside ophthalmology to develop strategies to address drug delivery to posterior intraocular tissues—a topic of great interest, as the major route of drug delivery is via intravitreous injection. Disciplines Medicine and Health Sciences | Ophthalmology | Pharmaceutics and Drug Design | Veterinary Medicine Comments Gustavo D. Aguirre is not listed as an individual author on this paper but is part of the Third ARVO/Pfizer Research Institute Working Group. A full list of the Third ARVO/Pfizer Research Institute Working Group members for this paper can be found on p.4713. This journal article is available at ScholarlyCommons: http://repository.upenn.edu/vet_papers/110 Drug Delivery to Posterior Intraocular Tissues: Third Annual ARVO/Pfizer Ophthalmics Research Institute Conference Henry F. Edelhauser1, Jeffrey H. Boatright1, John M. Nickerson1, and Third ARVO/Pfizer Research Institute Working Group2 1From the Department of Ophthalmology, Emory University, Atlanta, Georgia The third Annual ARVO/Pfizer Ophthalmic Research Institute Conference was held Friday and Saturday, May 4 and 5, 2007 at the Fort Lauderdale Grande Hotel and Yacht Club, Fort Lauderdale, Florida. The conference, funded by the ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics, provided an opportunity to gather experts from within and outside ophthalmology to develop strategies to address drug delivery to posterior intraocular tissues—a topic of great interest, as the major route of drug delivery is via intravitreous injection. A working group of 33 participants, focused interdisciplinary contributors, 19 observers from ARVO/Pfizer, and clinical and basic ophthalmic researchers convened to identify (1) unmet patient needs regarding current drug delivery, novel treatment of retinal diseases, the potential for novel drug design opportunities, drug delivery methods for targeted localized and sustained release, and delivery of macromolecules (siRNA, DNA); and (2) to evaluate the usefulness of nanoparticles, microbeads, and implants for drug delivery, as well as physical means of drug delivery (ionophoresis, electroporation, and microneedles). Session I: Unmet Needs and New Drug Opportunities in Treating Disorders of the Posterior Segment Session II: Animal Models of Posterior Ocular Diseases Session III: New Drug Design and Delivery Systems: What Do Experts See Beyond the Horizon? Session IV: Ocular Drug Delivery Using Nanoparticles, Microbeads, and Microneedles Session V: Transscleral, Intravitreous, and Suprachoroidal Drug Delivery Session VI: Ocular Tissue Dissection, Modeling, and Ocular Tissue Assays Session VII: Iontophoresis, Electroporation, Electrophoresis, and Photo-acoustic Delivery Each session began with a 10-minute introduction followed by a 30-minute lecture by a distinguished expert. Allan S. Hoffman, ScD, Professor of Bioengineering at the University of Washington, Seattle, presented “Design of Polymer Carriers for Intracellular Delivery of Biomolecular Drugs” and Mansoor Amiji, RPh, PhD, Professor and Associate Chairman of Pharmaceutical Science at Northeastern University (Boston, MA), presented “Nanotechnology for Advanced Drug Delivery.” Corresponding author: Herbert F. Edelhauser, Emory Eye Center, Suite B2600; 1365B Clifton Road, NE, Atlanta, GA, 30322; [email protected]. 2Members of the ARVO/Pfizer Research Institute Working Group are listed on page 4713 Disclosure: H.F. Edelhauser, Alcon (C, F, I); J.H. Boatright, None; J.M. Nickerson, None Published in final edited form as: Invest Ophthalmol Vis Sci. 2008 November ; 49(11): 4712–4720. doi:10.1167/iovs.08-1904. During the remainder of each session, participants, and attendees discussed pertinent questions, voiced opinions, and identified unanswered questions. These discussions confirmed current and future needs for ocular drug delivery to the posterior segment. Ocular Drug Delivery Overview Paul Sternberg, Jr, MD, summarized the clinical perspective of ocular drug delivery. Traditional means of drug delivery to the eye have involved topical medications, applied either in eye-drop or ointment form, supplemented with systemic medications such as antibiotics or corticosteroids. To achieve higher intraocular penetration, physicians began using subconjunctival and then sub-Tenon injections. However, it was demonstrated in the 1980s that adequate levels of antibiotics to treat endophthalmitis were achievable only with intravitreous injection. The Endophthalmitis Vitrectomy Study showed that supplemental use of intravenous antibiotics did not offer additional benefit. With the emergence of infectious retinitis associated with AIDS and the need for chronic antiviral therapy, investigators developed the Vitrasert (Bausch & Lomb, Rochester, NY), the first FDA-approved device for sustained delivery of intraocular medication. Many chronic ocular diseases require long-term therapy (glaucoma, AMD, diabetic retinopathy, uveitis, intraocular malignancy); review of the recent literature reveals a dramatic increase in studies evaluating novel methods for drug delivery.1–3 Clinicopathologic considerations of drug delivery for posterior segment diseases was summarized by Hans Grossniklaus, MD, MBA. Posterior segment diseases may generally be classified as inflammations, degenerations, and neoplasms. Drug delivery should be targeted to a particular coat (layer) of the eye, including the outer coat (sclera/cornea), middle coat (uveal tract), inner coat (retina), and vitreous. Posterior segment drug delivery for inflammatory conditions, both noninfectious and infectious, should minimize collateral damage, and duration should be timed in accordance with the acute or chronic nature of the disease. In proliferative diabetic retinopathy, drugs may be delivered via and/or targeted to neovascular tissue. In choroidal neovascularization (CNV), such as occurs in age-related macular degeneration (AMD), the growth pattern and stage of the CNV should be considered when designing drug delivery strategies. For instance, occult CNV grows between the retinal pigment epithelium (RPE) and Bruch's membrane; thus, transscleral or transuveal delivery may be desirable. However, classic CNV grows between the RPE and neurosensory retina; thus, transvitreal or subretinal delivery may be desirable. Typical CNV in patients with AMD has both sub-RPE and subretinal components. Primary intraocular large cell lymphoma grows within the retina around vascular channels and in the sub-RPE space, where it receives nutrition from the choriocapillaris. Lymphoma cells become apoptotic at approximately 90 to 110 μm external to the retinal vessels in the vitreous and choriocapillaris in the sub-RPE space, thus limiting the utility for local drug delivery. Similarly, retinoblastoma typically becomes necrotic at the same distance from its vascular supply, thus enabling the efficacy of systemic chemoreduction therapy in combination with local therapy. The exception in retinoblastoma is intravitreous seeding, which is notoriously unresponsive to chemoreduction and local therapy. Local carboplatin injection for intravitreous seeds may lead to ischemic optic neuropathy, thus indicating that advances in local drug delivery are necessary. In most instances, uveal melanoma may be locally controlled with radioactive plaque brachytherapy, proton beam irradiation, and/or TTT. However, exceptions include plaque failures, collateral radiation, retinopathy/optic neuropathy, and TTT failures, thus favoring the utility of local drug delivery. Local drug delivery must be superior to currently available treatments, cause minimal collateral damage, and be based on the pathobiology of the disease. 2007 Third ARVO/Pfizer Ophthalmics Research Institute Working Group Participants Edelhauser et al. Page 2 Invest Ophthalmol Vis Sci. Author manuscript; available in PMC 2009 August 1. Gary Abrams, Wayne State University, Detroit, MI Anthony Adamis, (OSI) Eyetech, New York, NY Gustavo D. Aguirre, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA Jayakrishna Ambati, University of Kentucky, Lexington, KY Patricia Becerra, National Eye Institute (NEI), Bethesda, MD Francine Behar-Cohen, Institut National de la Santé et de la Recherche Médicale [INSERM], Paris, France Lennart Berglin, Karolinska Institute/St. Eriks Eye Hospital, Stockholm, Sweden Steven Bernstein, University of Maryland School of Medicine at Baltimore, Baltimore, MD Jeffrey Boatright, Emory University Eye Center, Atlanta, GA Rosalie Crouch, Medical University of South Carolina, Charleston, SC Henry F. Edelhauser, Emory University Eye Center, Atlanta, GA William Freeman, University of California-San Diego, San Diego, CA Martin Friedlander, Scripps Research Institute, La Jolla, CA Dayle Geroski, Emory University Eye Center, Atlanta, GA Hans Grossniklaus, Emory University Eye Center, Atlanta, GA John Heckenlively, University of Michigan, Ann Arbor, MI John Kempen, University of Pennsylvania School of Medicine, Philadelphia, PA Uday Kompella, University of Nebraska Medical Center, Omaha, NE Alan Laties, University of Pennsylvania School of Medicine, Philadelphia, PA Matthew LaVail, University of California, San Francisco School of Medicine, San Francisco, CA James McGinnis, University of Oklahoma, Oklahoma City, OK Robert Marc, University of Utah, Salt Lake City, UT Joan Miller, Massachusetts Eye & Ear Infirmary, Boston, MA John Nickerson, Emory University Eye Center, Atlanta, GA Joan O'Brien, University of California, San Francisco School of Medicine, San Francisco, CA Timothy Olsen, University of Minnesota, Minneapolis, MN Daniel Palanker, Stanford University, Stanford, CA Michael Robinson, Allergan, Irvine, CA David Saperstein, University of Washington, Seattle, WA Paul Sternberg, Jr, Vanderbilt Eye Institute, Nashville, TN J. Tim Stout, Oregon Health and Science University, Portland, OR George Williams, Beaumont Eye Institute, Royal Oak, MI Edelhauser et al. Page 3 Invest Ophthalmol Vis Sci. Author manuscript; available in PMC 2009 August 1. Thomas Yorio, University of North Texas Health Science Center, Fort Worth, TX.. Unmet Needs and New Drug Opportunities in Treating Disorders of the Posterior Segment George Williams, MD, emphasized the need for advances in drug delivery to treat retinal disease. Diseases of the posterior segment represent the leading cause of visual impairment and blindness in the United States. Until recently, treatment of most posterior segment disorders has been primarily surgical: laser photocoagulation for retinal vascular disease and vitrectomy for vitreopathies. Over the past few years, improved understanding of the pathophysiology of many retinal diseases has led to development of effective novel drug therapies, which in some diseases have replaced surgical therapies and in others, complement surgery. Increasingly, the combination of surgery and drug-based therapy addresses retinal disease at both the anatomic and molecular level, resulting in improved visual outcomes. Despite the relative success of these novel drugs, important problems and new issues related to drug delivery remain. The explosion in the use of intravitreous drugs carries the potential of ocular and even systemic complications. The need for repeated intravitreous injections over the course of months and years creates a significant treatment burden for patients and their families. Improved drug delivery technologies that provide optimal pharmacokinetics, dose intervals, and less invasive routes of administration are needed. Interdisciplinary Contributors Mansoor Amiji, Northeastern University, Boston, MA Allan Hoffman, University of Washington, Seattle, WA Kevin Li, University of Cincinnati, Cincinnati, OH Paul Missel, Alcon Research, Ltd., Fort Worth, TX Mark Prausnitz, Georgia Institute of Technology, Atlanta, GA