Computational Fluid Dynamics Modeling of Intravitreal Ranibizumab Bolus Versus Subretinal ABBV-RGX-314 Transgene Product in Human Eyes.

IF 2.6 3区医学 Q2 OPHTHALMOLOGY

Translational Vision Science & Technology Pub Date : 2025-10-01 DOI:10.1167/tvst.14.10.6

Jenny Park, Mohammad Kazemi, Mitalee Tamhane, Jie Shen

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引用次数: 0

Abstract

Purpose: ABBV-RGX-314 is being developed for neovascular age-related macular degeneration (nAMD). Computational fluid dynamics (CFDs) modeling in the eye enables simulation of drug distribution incorporating geometry and substructures of the eye across species. Given the similarity between ranibizumab and ABBV-RGX-314 transgene product (TP), ranibizumab intraocular pharmacokinetic (PK) data from literature were used to simulate intraocular drug distribution of ABBV-RGX-314 TP. This investigation aims to use CFD modeling to estimate retinal TP level based on aqueous humor (AH) TP level following subretinal (SR) injection of ABBV-RGX-314 in patients with nAMD.

Methods: Ocular distribution of ranibizumab following a single intravitreal (IVT) injection was modeled in both monkey and human eyes independently. Following model validation, ABBV-RGX-314 TP distribution in human eyes was simulated following retinal transduction of ABBV-RGX-314.

Results: Iterative simulations were performed to achieve similar AH ABBV-RGX-314 TP levels in patients with nAMD from phase I/IIa Study RGX-314-001. The CFD simulation estimated corresponding retinal TP concentrations of 1.86 to 5.50 µg/g at steady-state, which was assumed to be reached by 28 days and falls within the range of the estimated retinal ranibizumab trough retinal ranibizumab concentration (Ctrough; 0.718-5.37 µg/g) following monthly and every other month (EOM) dosing of 0.5 mg ranibizumab in patients with nAMD.

Conclusions: The current study results predict that the 2 pivotal trial ABBV-RGX-314 doses (6.4E10 and 1.3E11 genome copies/eye) are expected to achieve and maintain sufficient retinal ABBV-RGX-314 TP levels for the treatment of nAMD.

Translational relevance: CFD modeling effectively bridges limited human ocular PK data with rich preclinical data, supporting model-informed drug development (MIDD) for clinical dose selection.

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人眼玻璃体内注射雷尼单抗与视网膜下ABBV-RGX-314转基因产品的计算流体动力学建模。

目的：ABBV-RGX-314正在开发用于新生血管性年龄相关性黄斑变性（nAMD）。眼睛中的计算流体动力学（cfd）建模可以模拟药物分布，包括不同物种眼睛的几何和亚结构。鉴于雷尼单抗与ABBV-RGX-314转基因产物（TP）的相似性，我们利用文献中雷尼单抗眼内药代动力学（PK）数据模拟ABBV-RGX-314 TP的眼内药物分布。本研究旨在利用CFD模型估算nAMD患者视网膜下（SR）注射ABBV-RGX-314后，基于房水（AH） TP水平的视网膜TP水平。方法：单次玻璃体内注射雷尼单抗后，分别在猴眼和人眼中建立了雷尼单抗的眼部分布模型。在模型验证后，模拟ABBV-RGX-314在视网膜转导后在人眼中的TP分布。结果：通过反复模拟，在I/IIa期研究RGX-314-001的nAMD患者中获得类似的AH ABBV-RGX-314 TP水平。CFD模拟估计稳态下相应的视网膜TP浓度为1.86至5.50µg/g，假设在28天内达到，并且在nAMD患者每月和每隔一个月（EOM）给药0.5 mg雷尼单抗后，通过视网膜雷尼单抗浓度（Ctrough; 0.718-5.37µg/g）估计的视网膜雷尼单抗范围内。结论：目前的研究结果预测，2个关键试验ABBV-RGX-314剂量（6.4E10和1.3E11基因组拷贝/眼）有望达到并维持足够的视网膜ABBV-RGX-314 TP水平，用于治疗nAMD。翻译相关性：CFD建模有效地将有限的人眼PK数据与丰富的临床前数据联系起来，支持模型知情药物开发（MIDD）进行临床剂量选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Vision Science & Technology Engineering-Biomedical Engineering

CiteScore

5.70

自引率

3.30%

发文量

346

审稿时长

25 weeks

期刊介绍： Translational Vision Science & Technology (TVST), an official journal of the Association for Research in Vision and Ophthalmology (ARVO), an international organization whose purpose is to advance research worldwide into understanding the visual system and preventing, treating and curing its disorders, is an online, open access, peer-reviewed journal emphasizing multidisciplinary research that bridges the gap between basic research and clinical care. A highly qualified and diverse group of Associate Editors and Editorial Board Members is led by Editor-in-Chief Marco Zarbin, MD, PhD, FARVO. The journal covers a broad spectrum of work, including but not limited to: Applications of stem cell technology for regenerative medicine, Development of new animal models of human diseases, Tissue bioengineering, Chemical engineering to improve virus-based gene delivery, Nanotechnology for drug delivery, Design and synthesis of artificial extracellular matrices, Development of a true microsurgical operating environment, Refining data analysis algorithms to improve in vivo imaging technology, Results of Phase 1 clinical trials, Reverse translational ("bedside to bench") research. TVST seeks manuscripts from scientists and clinicians with diverse backgrounds ranging from basic chemistry to ophthalmic surgery that will advance or change the way we understand and/or treat vision-threatening diseases. TVST encourages the use of color, multimedia, hyperlinks, program code and other digital enhancements.