Ocular Pharmacokinetics and Drug Delivery Challenges
Chorioretinal vascular conditions are among the leading causes of blindness throughout the developed world. Patients usually lose vision because of breakdown of the blood-retinal barrier or complications of neovascularization, two consequences of angiogen
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Ocular Pharmacokinetics and Drug Delivery Challenges Michael W. Stewart
Contents 1 Introduction 2 Important Ocular Anatomy 2.1 Gross Anatomy 2.2 Tear Film 2.3 Sclera 2.4 Choroid 2.5 Retina 2.6 Vitreous 2.7 Blood-Retinal Barrier 2.8 Melanin Binding 3 Ocular Pharmacokinetics 3.1 Basic Pharmacokinetics 3.2 Topical Therapy 3.3 Drug Development and Pharmacokinetics 4 Pharmacodynamics 4.1 Preclinical Studies 5 Challenges to Drug Delivery 5.1 Drugs that Possess Extended Durations of Action 5.2 Encapsulated Cell Technology 5.3 Gene Therapy 5.4 Refillable Implant 5.5 Small Molecule Sustained Release Devices 6 Conclusion References
Abstract Chorioretinal vascular conditions are among the leading causes of blindness throughout the developed world. Patients usually lose vision because of breakdown of the blood-retinal barrier or complications of neovascularization, two consequences of angiogenesis. These pathophysiologic processes are driven by chemokines and cytokines (particularly vascular endothelial growth factor
M. W. Stewart (*) Department of Ophthalmology, Mayo School of Medicine, Jacksonville, FL, USA e-mail: [email protected]
M. W. Stewart
(VEGF)), which are upregulated by vascular and inflammatory damage to fragile tissues. For the past 15 years, the preferred treatment of these conditions has been the intravitreal injection of corticosteroids and drugs that inhibit the actions of VEGF. After intravitreal depot injections, anti-VEGF drugs reconstitute the blood-retinal barrier and inhibit the growth of neovascular complexes while causing significant vascular remodeling. Ranibizumab, aflibercept, and brolucizumab have been approved by the US FDA for the treatment of macular degeneration, whereas bevacizumab is often injected off-label. After intraocular injections, these drugs move through the vitreous and retina according to their size and charge until they bind VEGF and prevent its activation of trans-membrane receptors. The drugs are not metabolized within the eye, they exit primarily through the trabecular meshwork, and they are removed from the systemic circulation via the liver and kidneys. AntiVEGF drug developers are presently focused on extending the duration of VEGF inhibition with port (reservoir) delivery systems, encapsulated cell technology, nanoparticle technology, and gene therapy. Though several drugs have shown early promise, some have failed to produce an adequate clinical response, and none has successfully completely phase III trials. Keywords Angiogenesis, Drug delivery, Pharmacodynamics, Pharmacokinetics, Retina, Vascular endothelial growth factor
1 Introduction Retinal diseases are important causes of visual disability and blindness throughout the world, and though the list of important retinal diseases is extensive, the most important conditions can be broadly classified as vascular, infectious, inflammatory, and degenerative. Choroidal and retinal vascular diseases such as exudative age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusions are am
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