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Computational Model of In Vivo Corneal Pharmacokinetics and Pharmacodynamics of Topically Administered Ophthalmic Drug Products

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Abstract

Introduction

Although the eye is directly accessible on the surface of the human body, drug delivery can be extremely challenging due to the presence of multiple protective barriers in eye tissues. Researchers have developed complex formulation strategies to overcome these barriers to ophthalmic drug delivery. Current development strategies rely heavily on in vitro experiments and animal testing to predict human pharmacokinetics (PK) and pharmacodynamics (PD).

Objective

The primary objective of the study was to develop a high-fidelity PK/PD model of the anterior eye for topical application of ophthalmic drug products.

Methods

Here, we present a physiologically-based in silico approach to predicting PK and PD in rabbits after topical administration of ophthalmic products. A first-principles based approach was used to describe timolol dissolution, transport, and distribution, including consideration of ionized transport, following topical instillation of a timolol suspension.

Results

Using literature transport and response parameters, the computational model described well the concentration–time and response-time profiles in rabbit. Comparison of validated rabbit model results and extrapolated human model results demonstrate observable differences in the distribution of timolol at multiple time points.

Conclusion

This modeling framework provides a tool for model-based prediction of PK in eye tissues and PD after topical ophthalmic drug administration to the eyes.

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Acknowledgements

We would like to thank Dr. Kay Sun and Mr. Joseph Pak for their early contributions to the project.

Funding

This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of two financial assistance awards [U01FD005219 and HHSF223201810151C] totaling $453,423 and $499,806 with 100 percent funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.

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Authors and Affiliations

  1. CFD Research Corporation, Computational Biology Division, 6820 Moquin Dr NW, Huntsville, AL, 35806, USA

    Carrie German, Zhijian Chen & Andrzej Przekwas

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

    Ross Walenga, Andrew Babiskin, Liang Zhao & Ming-Liang Tan

  3. Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA

    Jianghong Fan

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  1. Carrie German
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Correspondence to Carrie German.

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German, C., Chen, Z., Przekwas, A. et al. Computational Model of In Vivo Corneal Pharmacokinetics and Pharmacodynamics of Topically Administered Ophthalmic Drug Products. Pharm Res 40, 961–975 (2023). https://doi.org/10.1007/s11095-023-03480-6

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