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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-020-02946-1) contains supplementary material, which is available to authorized users.