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Application of Mechanistic Ocular Absorption Modeling and Simulation to Understand the Impact of Formulation Properties on Ophthalmic Bioavailability in Rabbits: a Case Study Using Dexamethasone Suspension

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Abstract

Developing mathematical models to predict changes in ocular bioavailability and pharmacokinetics due to differences in the physicochemical properties of complex topical ophthalmic suspension formulations is important in drug product development and regulatory assessment. Herein, we used published FDA clinical pharmacology review data, in-house, and literature rabbit pharmacokinetic data generated for dexamethasone ophthalmic suspensions to demonstrate how the mechanistic Ocular Compartmental Absorption and Transit model by GastroPlus™ can be used to characterize ocular drug pharmacokinetic performance in rabbits for suspension formulations. This model was used to describe the dose-dependent (0.01 to 0.1%) non-linear pharmacokinetic in ocular tissues and characterize the impact of viscosity (1.67 to 72.9 cP) and particle size (5.5 to 22 μm) on in vivo ocular drug absorption and disposition. Parameter sensitivity analysis (hypothetical suspension particle size: 1 to 10 μm, viscosity: 1 to 100 cP) demonstrated that the interplay between formulation properties and physiological clearance through drainage and tear turnover rates in the pre-corneal compartment drives the ocular drug bioavailability. The quick removal of drug suspended particles from the pre-corneal compartment renders the impact of particle size inconsequential relative to viscosity modification. The in vivo ocular absorption is (1) viscosity non-sensitive when the viscosity is high and the impact of viscosity on the pre-corneal residence time reaches the maximum physiological system capacity or (2) viscosity sensitive when the viscosity is below a certain limit. This study reinforces our understanding of the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug PK performance in rabbits.

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Author information

Authors and Affiliations

  1. Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Maxime Le Merdy, Jianghong Fan, Eleftheria Tsakalozou, Andrew Babiskin & Liang Zhao

  2. Simulations Plus, Inc., 42505 10th Street West, Lancaster, California, 93534, USA

    Michael B. Bolger, Viera Lukacova & Jessica Spires

  3. Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Vikram Patel, Lin Xu, Sharron Stewart, Ashok Chockalingam, Suresh Narayanasamy, Rodney Rouse & Murali Matta

  4. Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Darby Kozak

  5. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Stephanie Choi, Lei Zhang & Robert Lionberger

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  1. Maxime Le Merdy
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Correspondence to Jianghong Fan.

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Le Merdy, M., Fan, J., Bolger, M.B. et al. Application of Mechanistic Ocular Absorption Modeling and Simulation to Understand the Impact of Formulation Properties on Ophthalmic Bioavailability in Rabbits: a Case Study Using Dexamethasone Suspension. AAPS J 21, 65 (2019). https://doi.org/10.1208/s12248-019-0334-x

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