A first passage model of intravitreal drug delivery and residence time, in relation to ocular geometry, individual variability, and injection location

Purpose: Standard of care for various retinal diseases involves recurrent intravitreal injections. This motivates mathematical modelling efforts to identify influential factors for drug residence time, aiming to minimise administration frequency. We sought to describe the vitreal diffusion of therapeutics in nonclinical species used during drug development assessments. In human eyes, we investigated the impact of variability in vitreous cavity size and eccentricity, and in injection location, on drug elimination. Methods: Using a first passage time approach, we modelled the transport-controlled distribution of two standard therapeutic protein formats (Fab and IgG) and elimination through anterior and posterior pathways. Detailed anatomical 3D geometries of mouse, rat, rabbit, cynomolgus monkey, and human eyes were constructed using ocular images and biometry datasets. A scaling relationship was derived for comparison with experimental ocular half-lives. Results: Model simulations revealed a dependence of residence time on ocular size and injection location. Delivery to the posterior vitreous resulted in increased vitreal half-life and retinal permeation. Interindividual variability in human eyes had a significant influence on residence time (half-life range of 5-7 days), showing a strong correlation to axial length and vitreal volume. Anterior exit was the predominant route of drug elimination. Contribution of the posterior pathway displayed a small (3%) difference between protein formats, but varied between species (10-30%). Conclusions: The modelling results suggest that experimental variability in ocular half-life is partially attributed to anatomical differences and injection site location. Simulations further suggest a potential role of the posterior pathway permeability in determining species differences in ocular pharmacokinetics.