Evaluating bioequivalence of ophthalmic drug products in humans is challenging for ethical and practical reasons. Often, animal models are used to evaluate ophthalmic bioequivalence. Unfortunately, methods for translation of animal model results to humans has proven elusive. There is a critical need to develop computational tools to assist with interspecies translation. Physiologically-based model extrapolation can provide a means for explaining interspecies differences in pharmacokinetics (PK) and pharmacodynamics (PD). The objective of the proposed work is to develop a translational tool framework for capturing interspecies differences in the PK and PD of ophthalmic drug products using physiologically-based model extrapolation methods. To facilitate framework development, we will collect physiologically-based rabbit and human ophthalmic PK and PD models from literature. Model components will be integrated with our existing models to create optimized models. Our team?s experience in multiscale ophthalmic modeling enables the framework to include models of varying complexity (compartmental, quasi-3D, 2D and novel 2.5D models), which provides are more complete picture of potential extrapolation solutions versus implementing a single model type. Model details (i.e. modeled tissues, segment, complexity, physiological phenomena, etc.) will be organized in a spreadsheet which will include model capabilities and limitations. In parallel, an opensource database comparing rabbit and human anatomical and physiological parameter values/value ranges will be created. Collected and optimized rabbit PK and PD models will be extrapolated/scaled up to human models by changing anatomical, physiological and biophysical parameter values. Common dosing scenarios (topical and intravitreal administration of solutions, solid suspensions and emulsions) will be simulated using extrapolated, collected and optimized human ophthalmic PK and PD models for comparison purposes. Comparison of simulation results will enable identification of the current translational knowledge gaps. The framework will allow evaluation of potential solutions to closing these knowledge gaps. This project will enhance public health by improving regulatory confidence, speed and efficiency in the approval process for new and generic ophthalmic drug products and by decreasing costs to the public.

Public Health Relevance

The proposed project addresses the critical need for the development of computational tools to translate preclinical testing results from animals to humans for ophthalmic drug products. This project will provide researchers with a better understanding of the specific differences between animal and human eyes that result in differences in ocular drug distribution. This project will enhance public health by improving regulatory confidence, speed and efficiency in the approval process for new and generic ophthalmic drug products and decreasing costs to the public.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1)
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Tan, Mingliang
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Cfd Research Corporation
United States
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