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
Autor: | Sharron Stewart, Eleftheria Tsakalozou, Maxime Le Merdy, Murali K. Matta, Andrew Babiskin, Liang Zhao, Jianghong Fan, Suresh Narayanasamy, Lei Zhang, Ashok Chockalingam, Jessica Spires, Darby Kozak, Vikram Patel, Stephanie Choi, Lin Xu, Rodney Rouse, Robert Lionberger, Michael B. Bolger, Viera Lukacova |
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Rok vydání: | 2018 |
Předmět: |
Drug
Absorption (pharmacology) media_common.quotation_subject Ocular Absorption Pharmaceutical Science Biological Availability Bioequivalence Eye 030226 pharmacology & pharmacy Models Biological Dexamethasone 03 medical and health sciences Viscosity 0302 clinical medicine Pharmacokinetics Suspensions In vivo Animals Humans Computer Simulation media_common Dose-Response Relationship Drug Chemistry eye diseases Bioavailability 030220 oncology & carcinogenesis Biophysics sense organs Rabbits Ophthalmic Solutions |
Zdroj: | The AAPS journal. 21(4) |
ISSN: | 1550-7416 |
Popis: | 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. |
Databáze: | OpenAIRE |
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