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The AAPS Journal

, 21:65 | Cite as

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

  • Maxime Le Merdy
  • Jianghong FanEmail author
  • Michael B. Bolger
  • Viera Lukacova
  • Jessica Spires
  • Eleftheria Tsakalozou
  • Vikram Patel
  • Lin Xu
  • Sharron Stewart
  • Ashok Chockalingam
  • Suresh Narayanasamy
  • Rodney Rouse
  • Murali Matta
  • Andrew Babiskin
  • Darby Kozak
  • Stephanie Choi
  • Lei Zhang
  • Robert Lionberger
  • Liang Zhao
Research Article
  • 538 Downloads

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.

KEY WORDS

bioequivalence dexamethasone ocular PBPK particle size simulation viscosity 

Notes

Compliance with Ethical Standards

Disclaimer

This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Supplementary material

12248_2019_334_MOESM1_ESM.docx (85 kb)
ESM 1 (DOCX 85 kb)
12248_2019_334_MOESM2_ESM.docx (23 kb)
ESM 2 (DOCX 23 kb)
12248_2019_334_MOESM3_ESM.docx (17 kb)
ESM 3 (DOCX 17 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Maxime Le Merdy
    • 1
  • Jianghong Fan
    • 1
    Email author
  • Michael B. Bolger
    • 2
  • Viera Lukacova
    • 2
  • Jessica Spires
    • 2
  • Eleftheria Tsakalozou
    • 1
  • Vikram Patel
    • 3
  • Lin Xu
    • 3
  • Sharron Stewart
    • 3
  • Ashok Chockalingam
    • 3
  • Suresh Narayanasamy
    • 3
  • Rodney Rouse
    • 3
  • Murali Matta
    • 3
  • Andrew Babiskin
    • 1
  • Darby Kozak
    • 4
  • Stephanie Choi
    • 5
  • Lei Zhang
    • 5
  • Robert Lionberger
    • 5
  • Liang Zhao
    • 1
  1. 1.Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic DrugsCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  2. 2.Simulations Plus, Inc.LancasterUSA
  3. 3.Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational SciencesCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  4. 4.Division of Therapeutic Performance, Office of Research and Standards, Office of Generic DrugsCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  5. 5.Office of Research and Standards, Office of Generic DrugsCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA

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