Determination of Human Effective Dose via Translational Ocular Modeling: Clinical Translation of a Novel Topical Agent Using PBPK.

Wet age-related macular degeneration (wAMD) is a leading cause of vision loss, and human dose selection for ocular therapeutics remains a key translational challenge. We developed a physiologically based pharmacokinetic (PBPK) model for EB-203 to guide dose selection by translating preclinical ocular tissue exposure to human. PK data were obtained from mouse and rabbit studies and human plasma PK from a phase I trial. The model incorporated species-specific ocular physiology, drug permeability, and pharmacokinetics, and was implemented using an open-source PBPK modeling software (MoBi, version 12.2, Open Systems Pharmacology). Drug-specific model parameters were estimated using mouse and rabbit plasma and ocular tissue concentration data. Human plasma PK data from a Phase I clinical trial were then used to estimate human-specific systemic clearance, and human ocular tissue concentrations were subsequently predicted by the model. Simulated human retinal drug concentrations (AUC, Cmax, and Cavr) under multiple dosing regimens were evaluated against preclinical efficacy thresholds to determine the optimal dosing strategy. The model adequately described drug disposition across species, with most predicted PK parameters falling within a 2-fold error of the observed data. Simulations suggested that a 4% four-times-daily dosing regimen in humans achieves retinal exposure comparable to the efficacious mouse concentrations. No significant systemic accumulation was observed, indicating a favorable safety profile. This PBPK framework provides a practical approach for predicting human ocular drug exposure and can be adapted to other compounds or ocular indications in the absence of direct tissue sampling. These results support further clinical evaluation of EB-203 for the treatment of wAMD.