BackgroundFor approval, a generic drug product must demonstrate it is bioequivalent (BE) to the (brand name) reference listed drug (RLD) product.

For locally acting drug products, where conventional BE approaches are infeasible, the FDA has been researching the feasibility of alternative, scientifically

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valid methods, including modeling approaches, to support an evaluation of BE.Ophthalmic drugs are locally acting and may give rise to challenges in measuring detectable drug levels.

To establish BE of ophthalmic drug products, a comparative clinical endpoint BE study is generally utilized as a surrogate for drug concentration at the site of action, as such measurements in local eye tissues are often impractical, unethical and cost-prohibitive.

Modeling and simulation can be a powerful tool to predict local drug concentrations in eye tissues based on data from in vitro, animal, and human studies.

Specifically, physiologically-based pharmacokinetic (PBPK) modeling may integrate information about the drug product properties and ocular physiology to predict the pharmacokinetics (PK) and pharmacodynamics (PD) in humans, allowing clinical relevance determination of critical drug product attributes for BE assessment.

To advance FDA's mission to make high quality, safe, and effective drug products available to the American public while supporting innovation, it is essential to explore the potential utility of novel, efficient standards for BE that may be applicable to prospective generic drug products.

To support this goal, the Agency seeks to investigate the qualitative and functional characteristics of different ophthalmic formulations and to understand when differences in product quality attributes may be clinically meaningful, by utilizing modeling and simulation approaches.ObjectiveThe objective of this work is to support research relevant to ophthalmic drug products that will help extrapolate animal models to human ophthalmic PK and PD models.

The purpose is to systematically evaluate the current animal and human ophthalmic PK and PD models available, with a focus on extrapolation from existing animal models to human models.Upon the successful completion of this research, we would expect to have a better understanding of the current existing knowledge gaps and potential solutions for the human PK/PD model extrapolation from animal models.Detailed DescriptionPreclinical studies are very useful to understand drug absorption, distribution, metabolism and excretion (ADME).

The rabbit is commonly used in ophthalmic drug development due to the similarity in anatomy and physiology between rabbit and human eyes.

Drug concentrations in rabbit local eye tissues, such as aqueous humor, iris ciliary body, cornea and conjunctiva, can be measured.

This in vitro and animal data can be used to develop PK and PD models that can be further verified and validated using additional animal data during the rabbit model development.Human PBPK/PD models can be extrapolated from validated animal models by considering the anatomy and physiology differences between rabbit and human eyes.

However, one of the major challenges is the validation of the extrapolated PK and PD models because human data are sparsely available.

The measurement of drug in most ocular tissues is infeasible in clinical studies.

Drug concentrations may be measured in aqueous humor but obtaining samples can only be justified during cataract surgery for cataract patients only.

For PD measurement, intra-ocular pressure (IOP) currently remains to be the only known modifiable risk factor for open-angle glaucoma.

Measurement of IOP reduction has been used in preclinical and clinical settings to evaluate the efficacy for anti-glaucoma drug products.This research would aim to systematically evaluate the current animal and human ophthalmic PK and PD models available, with a focus on the extrapolation from existing animal models to human PK and PD models, validating the human model, and understanding knowledge gaps and potential solutions for successful model extrapolation.Specific aims include:
1. Develop a comprehensive report detailing the rabbit ophthalmic PK and PD models and pre-clinical data available.

2. Develop a comprehensive report detailing the human ophthalmic PK and PD models and the related clinical data available.

3. Extrapolate rabbit PK and PD models in Aim 1 to human PBPK/PD models by considering the anatomy and physiology differences between rabbits and human beings.

4. Compare and verify the human PK and PD models developed in Aim 3 with human models collected in Aim 2. Evaluate the knowledge gaps and potential solutions in the rabbit-to-human scale up.

5. Preparation of manuscripts, which is intended to be done in the third year of the grant, and is the reason for the reduced budget for that year.

This phase may also begin earlier than the third year.