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Pharmacokinetic Aspects of Retinal Drug Delivery

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Pharmacokinetic Aspects of Retinal Drug Delivery Progress in Retinal and Eye Research 57 (2017) 134e185 Contents lists available at ScienceDirect Progress in Retinal and Eye Research journal homepage: www.elsevier.com/locate/prer Pharmacokinetic aspects of retinal drug delivery Eva M. del Amo b, 1, Anna-Kaisa Rimpela€ a, 1, Emma Heikkinen b, 1, Otto K. Kari a, 1, Eva Ramsay b, 1, Tatu Lajunen a, 1, Mechthild Schmitt a, 1, Laura Pelkonen b, 1, Madhushree Bhattacharya a, 1, Dominique Richardson a, 1, Astrid Subrizi b, 1, Tiina Turunen a, 1, Mika Reinisalo b, 1, Jaakko Itkonen a, 1, Elisa Toropainen b, 1, Marco Casteleijn a, 1, Heidi Kidron a, 1, Maxim Antopolsky a, 1, Kati-Sisko Vellonen b, 1, * Marika Ruponen b, 1, Arto Urtti a, b, a Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland b School of Pharmacy, University of Eastern Finland, Kuopio, Finland article info abstract Article history: Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many Received 23 August 2016 diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal in- Received in revised form jections are the method of choice to administer drugs to the retina, but this approach is applicable only in 25 November 2016 selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be Accepted 1 December 2016 adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs Available online 24 December 2016 and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety Keywords: Retina of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates Vitreous and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in Choroid ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly Topical from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery Intravitreal technologies, because they have already been reviewed several times recently. Instead, we aim to provide a Sub-conjunctival systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye Suprachoroidal segment. This review is based on the literature and unpublished data from the authors' laboratory. Clearance © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND Distribution license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Pharmacokinetic modeling Transport Contents 1. Introduction . ....................... 135 2. Blood-ocular barriers . ....................... 137 2.1. Inner blood retinal barrier: retinal capillaries . ......................................137 2.2. Outer blood retinal barrier: retinal pigment epithelium . ...........................137 2.3. Blood-aqueous barrier . ..........................................138 2.4. Active transport in blood-ocular barrier . ......................................138 2.5. Summary on barriers . ..........................................139 3. Intravitreal drug administration . ....................... 139 3.1. Drug distribution and interactions with the vitreous . ...........................139 3.1.1. Vitreous humor . ..........................................139 * Corresponding author. Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Viikinkaari 5 E, P.O. Box 56, 00790, Helsinki, Finland. E-mail addresses: arto.urtti@helsinki.fi, arto.urtti@uef.fi (A. Urtti). 1 Percentage of work contributed by each author in the production of the manuscript is as follows: Eva M. del Amo - 10%; Anna-Kaisa Rimpela - 10%; Emma Heikkinen - 5%; Otto k. Kari - 5%; Eva Ramsay - 4%; Tatu Lajunen - 4%; Mechthild Schmitt - 4%; Laura Pelkonen - 4%; Madhushree Bhattacharya - 4%; Dominique Richardson - 4%; Astrid Subrizi - 4%; Tina Turunen - 4%; Mika Reinisalo - 3%; Jaakko Itkonen - 3%; Elisa Toropainen - 3%; Marco Casteleijn - 2% Heidi Kidron - 2%; Maxim Antopolsky - 2%; Kati-Sisko Vellonen - 3%; Marika Ruponen - 5%. http://dx.doi.org/10.1016/j.preteyeres.2016.12.001 1350-9462/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). E.M. del Amo et al. / Progress in Retinal and Eye Research 57 (2017) 134e185 135 3.1.2. Diffusion in the vitreous . .......................139 3.1.3. Convection in the vitreous . .......................140 3.1.4. Drug interactions with the vitreous . .......................140 3.1.5. Distribution to the surrounding ocular tissues . .......................141 3.2. Drug elimination from the vitreous . .......................142 3.2.1. Metabolic drug elimination . .......................142 3.2.2. Drug elimination through blood-ocular barriers . .......................142 3.2.3. Elimination via anterior route . .......................144 3.2.4. Roles of blood-ocular barrier components in vitreal drug elimination . .......................144 3.2.5. Other mechanisms . .......................145 3.3. Drug delivery to the retinal layers from the vitreous . .......................145 3.3.1. The inner limiting membrane (ILM) . .......................145 3.3.2. Müller cells . .......................146 3.3.3. Outer limiting membrane (OLM) . .......................147 3.3.4. Summary . .. .......................147 3.4. Intravitreal drug delivery systems . .......................147 3.4.1. Macroscopic drug delivery systems . .......................147 3.4.2. Particulate drug delivery systems . .......................147 3.5. PK and PK/PD models for intravitreal drugs . .......................149 3.5.1. Models for drugs . .......................149 3.5.2. PK modeling in controlled release system design . .......................150 3.5.3. Degradation rate of polymers . .......................150 3.5.4. Relationship between drug solubility and release rate . .......................152 4. Systemic drug delivery to the retina . ........................................... 153 4.1. Drug distribution from blood circulation to the retina . .......................153 4.2. Retinal targeting from the blood stream . .......................156 5. Periocular drug administration . ............................................... 157 6. Suprachoroidal drug delivery . ............................................... 158 7. Sub-retinal drug delivery . ................................................ 160 8. Topical drug delivery . ................................................ 161 8.1. Drug absorption, distribution and efficacy . .......................161 8.2. Strategies for posterior segment drug delivery . .......................162 9. Retinal pharmacokinetics and drug delivery at cellular level . ................................... 163 9.1. Challenge of intracellular targets in the retina . ..
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