与眼部几何形状、个体差异及注射位置相关的玻璃体内给药和驻留时间的首过模型
A first passage model of intravitreal drug delivery and residence time, in relation to ocular geometry, individual variability, and injection location
AI总结：
本文提出一种基于首过时间的数学模型，研究眼部几何形状、个体差异及注射位置对玻璃体内药物驻留时间的影响，发现驻留时间与眼部尺寸和注射位置密切相关，且后房途径渗透性可能是导致物种间眼部药代动力学差异的潜在因素。
摘要：
目的：多种视网膜疾病的标准护理方法包括反复的玻璃体内注射。这促使我们开展数学建模工作，以确定影响药物驻留时间的关键因素，旨在减少给药频率。我们试图描述在药物开发评估期间使用的非临床物种中，治疗药物在玻璃体内的扩散情况。对于人类眼睛，我们研究了玻璃体腔大小和偏心率的变异性以及注射位置对药物消除的影响。方法：使用首过时间方法，我们模拟了两种标准治疗蛋白形式（Fab和IgG）的传输控制分布，以及通过前房和后房途径的消除过程。利用眼部图像和生物测量数据集，构建了小鼠、大鼠、兔子、食蟹猴和人类眼睛的详细解剖3D几何结构。推导出了一种比例关系，以便与实验测得的眼部半衰期进行比较。结果：模型模拟显示，驻留时间依赖于眼部大小和注射位置。向后部玻璃体给药会增加玻璃体内半衰期和视网膜渗透。人类眼睛的个体间差异对驻留时间有显著影响（半衰期范围为5-7天），且与眼轴长度和玻璃体体积呈强相关。前房途径是药物消除的主要途径。后房途径的贡献在不同蛋白形式之间显示出微小差异（3%），但在不同物种间存在差异（10-30%）。结论：建模结果表明，眼部半衰期的实验变异性部分归因于解剖差异和注射部位位置。模拟进一步表明，后房途径的渗透性在决定眼部药代动力学的物种差异方面可能具有潜在作用。
英文摘要：
Purpose: Standard of care for various retinal diseases involves recurrent intravitreal injections. This motivates mathematical modelling efforts to identify influential factors for drug residence time, aiming to minimise administration frequency. We sought to describe the vitreal diffusion of therapeutics in nonclinical species used during drug development assessments. In human eyes, we investigated the impact of variability in vitreous cavity size and eccentricity, and in injection location, on drug elimination. Methods: Using a first passage time approach, we modelled the transport-controlled distribution of two standard therapeutic protein formats (Fab and IgG) and elimination through anterior and posterior pathways. Detailed anatomical 3D geometries of mouse, rat, rabbit, cynomolgus monkey, and human eyes were constructed using ocular images and biometry datasets. A scaling relationship was derived for comparison with experimental ocular half-lives. Results: Model simulations revealed a dependence of residence time on ocular size and injection location. Delivery to the posterior vitreous resulted in increased vitreal half-life and retinal permeation. Interindividual variability in human eyes had a significant influence on residence time (half-life range of 5-7 days), showing a strong correlation to axial length and vitreal volume. Anterior exit was the predominant route of drug elimination. Contribution of the posterior pathway displayed a small (3%) difference between protein formats, but varied between species (10-30%). Conclusions: The modelling results suggest that experimental variability in ocular half-life is partially attributed to anatomical differences and injection site location. Simulations further suggest a potential role of the posterior pathway permeability in determining species differences in ocular pharmacokinetics.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
