Hutton-Smith Laurence A, Gaffney Eamonn A, Byrne Helen M, Maini Philip K, Gadkar Kapil, Mazer Norman A
Wolfson Centre For Mathematical Biology, Mathematical Institute, Andrew Wiles Building, University of Oxford , Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, U.K.
Department of Preclinical and Translational Pharmacokinetics, Genentech, Inc. , South San Francisco, California 94080, United States.
Mol Pharm. 2017 Aug 7;14(8):2690-2696. doi: 10.1021/acs.molpharmaceut.7b00164. Epub 2017 Jul 3.
Intravitreally (IVT) injected macromolecules for the treatment of age-related macular degeneration must permeate through the inner limiting membrane (ILM) into the retina and through the retinal pigment epithelium (RPE) to enter the choroid. A quantitative understanding of intraocular transport mechanisms, elimination pathways, and the effect of molecular size is currently incomplete. We present a semimechanistic, 3-compartment (retina, vitreous, and aqueous) pharmacokinetic (PK) model, expressed using linear ordinary differential equations (ODEs), to describe the molecular concentrations following a single IVT injection. The model was fit to experimental rabbit data, with Fab, Fc, IgG, and IgG null antibodies and antibody fragments, to estimate key ocular pharmacokinetic parameters. The model predicts an ocular half-life, t, which is the same for all compartments and dependent on the hydrodynamic radius (R) of the respective molecules, consistent with observations from the experimental data. Estimates of the permeabilities of the RPE and ILM are derived for R values ranging from 2.5 to 4.9 nm, and are found to be in good agreement with ex-vivo measurements from bovine eyes. We show that the ratio of these permeabilities largely determines the ratio of the molecular concentrations in the retina and vitreal compartments and their dependence on R. The model further provides estimates for the ratio of fluxes corresponding to the elimination pathways from the eye, i.e., aqueous humor to retina/choroid, which increase from 5:1 to 7:1 as R decreases. Our semimechanistic model provides a quantitative framework for interpreting ocular PK and the effects of molecule size on rate-determining parameters. We have shown that intraocular permeabilities can be reasonably estimated from 3-compartment ocular PK data and can determine how these parameters influence the half-life, retinal permeation, and elimination of intravitreally injected molecules from the eye.
玻璃体内（IVT）注射用于治疗年龄相关性黄斑变性的大分子必须透过内界膜（ILM）进入视网膜，并穿过视网膜色素上皮（RPE）进入脉络膜。目前对眼内转运机制、清除途径以及分子大小的影响尚缺乏定量认识。我们提出了一种半机制性的三室（视网膜、玻璃体和房水）药代动力学（PK）模型，用线性常微分方程（ODEs）表示，以描述单次IVT注射后的分子浓度。该模型与实验兔数据拟合，使用了Fab、Fc、IgG和IgG缺失抗体及抗体片段，以估计关键的眼药代动力学参数。该模型预测了一个眼内半衰期t，所有隔室的半衰期相同，且取决于各分子的流体动力学半径（R），这与实验数据的观察结果一致。对于R值在2.5至4.9纳米范围内，推导了RPE和ILM的渗透率估计值，发现与牛眼的离体测量结果高度一致。我们表明，这些渗透率的比值在很大程度上决定了视网膜和玻璃体隔室中分子浓度的比值及其对R的依赖性。该模型还提供了与眼内清除途径相对应的通量比值估计值，即房水与视网膜/脉络膜的通量比值，随着R的减小，该比值从5:1增加到7:1。我们的半机制性模型为解释眼内PK以及分子大小对速率决定参数的影响提供了一个定量框架。我们已经表明，可以从三室眼内PK数据合理估计眼内渗透率，并可以确定这些参数如何影响半衰期、视网膜渗透以及玻璃体内注射分子从眼内的清除。
