PI-101 - PREDICTING BRINZOLAMIDE OCULAR RESPONSE IN HUMANS USING AN OCULAR PBPK-PD MODELING AND SIMULATION

M. Le Merdy¹, J. Mullin², M. Tan³, V. Lukacova²; ¹Simulations Plus, Simulations Plus, Inc. Lancaster, CA., USA, ²Simulations Plus, Simulations Plus, Inc. Lancaster, CA., United States, ³U.S. Food and Drug Administration, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States of America.

Background: The development of generic ophthalmic drug products indicated for intraocular pressure (IOP) reduction typically relies on pharmacodynamic (PD) endpoint bioequivalence (BE) studies. These studies present challenges for the pharmaceutical industry due to their high costs and limited sensitivity to detect formulation differences between products and support BE. New BE methods are needed to support the development of generic IOP-reducing drug products. Brinzolamide (BRI) is a first-line medication for treating open-angle glaucoma and ocular hypertension. This study aims to demonstrate the ability of an ocular physiologically based pharmacokinetic (PBPK) and PD model to (1) predict ocular PK and PD in rabbits following topical administration of BRI suspension, and (2) predict ocular response in humans.

Methods: The physicochemical properties of BRI and its suspension, along with PK and PD data following topical ocular administration in rabbits and humans, were gathered from the literature. The Ocular Compartment Absorption and Transit (OCAT™) model within GastroPlus® v9.9 was initially used to describe the ocular PK profiles in rabbits. The PDPlus™ module within GastroPlus was then employed to model the effect of BRI on IOP in rabbits. After validating the PBPK-PD model in rabbits, it was applied to predict the observed PD in humans, with physiological parameters adjusted to reflect human physiology. All drug-specific PK and PD parameters, along with their associated variability, were maintained consistently across species.

Results: The OCAT model successfully described the observed BRI concentrations in the anterior segment tissues of the rabbit eye. The PD model provided accurate simulations of BRI’s observed reduction in IOP in rabbits. Following this validation, the ocular PBPK-PD model was used to predict BRI’s PD effect in humans when administered twice (Figure 1) or three times daily for six months.

Conclusion: This case study demonstrates the ocular PBPK-PD model’s capability to describe IOP reduction following BRI administration in rabbits. Additionally, it highlights the model's ability to predict the PD effect in humans using a mechanistic, model-based preclinical-to-clinical translation approach. This methodology could significantly influence the development of both new and generic ophthalmic drug products.