Extended Pharmacokinetic Model of the Intravitreal Injections of Macromolecules in Rabbits. Part 2: Parameter Estimation Based on Concentration Dynamics in the Vitreous, Retina, and Aqueous Humor.

Purpose: To estimate the diffusion coefficients of an IgG antibody (150 kDa) and its antigen-binding fragment (Fab; 50 kDa) in the neural retina (D _ret ) and the combined retinal pigment epithelium-choroid (D _RPE-cho ) with a 3-dimensional (3D) ocular pharmacokinetic (PK) model of the rabbit eye.
Methods: Vitreous, retina, and aqueous humor concentrations of IgG and Fab after intravitreal injection in rabbits were taken from Gadkar et al. (2015). A least-squares method was used to estimate D _ret and D _RPE-cho with the 3D finite element model where mass transport was defined with diffusion and convection. Different intraocular pressures (IOP), initial distribution volumes (V _init ), and neural retina/vitreous partition coefficients (K _ret/vit ) were tested. Sensitivity analysis was performed for the final model.
Results: With the final IgG model (IOP 10.1 Torr, V _init 400 μl, K _ret/vit 0.5), the estimated D _ret and D _RPE-cho were 36.8 × 10 ^-9 cm ² s ^-1 and 4.11 × 10 ^-9 cm ² s ^-1 , respectively, and 76% of the dose was eliminated via the anterior chamber. Modeling of Fab revealed that a physiological model parameter "aqueous humor formation rate" sets constraints that need to be considered in the parameter estimation.
Conclusions: This study extends the use of 3D ocular PK models for parameter estimation using simultaneously macromolecule concentrations in three ocular tissues.