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 cm²s⁻¹ and 4.11 × 10⁻⁹ cm²s⁻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.

中文翻译：

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家兔玻璃体内注射大分子的扩展药代动力学模型。第 2 部分：基于玻璃体、视网膜和房水浓度动态的参数估计

目的

使用 3估计 IgG 抗体 (150 kDa) 及其抗原结合片段 (Fab; 50 kDa) 在神经视网膜 (D _ret ) 和组合视网膜色素上皮-脉络膜 (D _RPE-cho ) 中的扩散系数兔眼三维 (3D) 眼药代动力学 (PK) 模型。

方法

家兔玻璃体内注射后玻璃体、视网膜和房水中 IgG 和 Fab 的浓度取自 Gadkar 等人。（2015）。使用最小二乘法通过 3D 有限元模型来估计 D _ret和 D _RPE-cho，其中通过扩散和对流定义质量传递。测试了不同的眼压（IOP）、初始分布体积（V _init）和神经视网膜/玻璃体分配系数（K _{ret/vit ）。}对最终模型进行了敏感性分析。

结果

使用最终的 IgG 模型（IOP 10.1 Torr，V _init 400 μl，K _ret/vit 0.5），估计的 D _ret和 D _RPE-cho分别为 36.8 × 10 ^-9 cm ² s ^-1和 4.11 × 10 ^-9 cm ² s ^-1，分别，76%的剂量通过前房消除。Fab 建模表明，生理模型参数“房水形成率”设置了参数估计中需要考虑的约束。

结论

这项研究扩展了 3D 眼部 PK 模型的使用，同时使用三种眼部组织中的大分子浓度进行参数估计。