  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.
