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 (DRPE-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 mu l, K(ret/vit)0.5), the estimated D(ret)and D(RPE-cho)were 36.8 x 10(-9)cm(2)s(-1)and 4.11 x 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.