Senior Research Scientist Certara UK Sheffield, England, United Kingdom
Background: The eye is a complex, highly specialized organ that is comprised of various static and dynamic barriers to drug delivery. Issues when studying the administration of drugs in clinical settings include: short time scales for exposure, and the difficulty of measuring exposure in vivo or ex vivo. Thus, the human eye is a particularly challenging organ in which to study pharmacokinetics (PK) experimentally. To overcome this limitation computational models of the eye have been developed, but current models are restrictive with respect to the region or compound of interest or can be too simplistic in their handling of a compound’s distribution within the eye. Methods: To overcome these limitations a physiologically based ocular PK model using 1D and 2D finite element approximations in anterior tissues was developed to model human eyes. To accurately model the diffusion of compounds of varying permeability across the cornea, a multi-layer compartmental model was used to describe the corneal epithelium and stroma. The aqueous humor is modelled using a radial 2D geometry that allows for accurate modelling of diffusion, temperature mediated fluid flow, and spatially accurate clearance. Results: The structural similarity with human eyes allowed for performance verification studies using atenolol and timolol in rabbits. The model obtains good agreement with experimental exposure data in different regions of the eye (see figure), even though many of the model input parameters – whose experimental values are unknown – were set to default values. A tight-bounded optimization of these parameters using Markov Chain-Monte Carlo sampling was performed, improving the agreement with experimental data significantly while keeping the parameters physically justifiable. Conclusion: A novel physiologically based PK model that accurately represents the permeation barriers and fluids of the anterior eye was developed. Simulated results in rabbits show a good degree of agreement with experimental results for compounds of varying hydrophobicity. Future work includes the expansion of finite element modelling to the posterior eye and preclinical to clinical translation.
