Three-Dimensional Transport Model for Intravitreal and Suprachoroidal Drug Injection
Three-Dimensional Transport Model for Intravitreal and Suprachoroidal Drug Injection
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DOI：
10.1167/iovs.17-23632
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发表时间：
2018-10
影响因子：
4.4
通讯作者：
Yu Zhang;H. Bazzazi;R. Lima e Silva;N. Pandey;J. Green;P. Campochiaro;A. Popel
中科院分区：
文献类型：
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作者：
Yu Zhang;H. Bazzazi;R. Lima e Silva;N. Pandey;J. Green;P. Campochiaro;A. Popel
目的定量了解眼内注射后治疗性大分子的转运对于设计治疗眼病的有效策略至关重要，如新生血管性（湿性）年龄相关性黄斑变性（AMD）和黄斑水肿（ME）。抗血管生成治疗，如针对VEGF的中和抗体或最近表征的抗血管生成肽，已显示出减缓疾病进展的希望。方法利用已发表的玻璃体腔和脉络膜上（SC）注射荧光素钠（SF）、贝伐单抗和雷尼单抗后兔眼内药物分布的数据，建立了一个全面的眼内注射三维（3D）转运模型。然后应用该模型评价玻璃体内和SC注射后人眼小分子和抗血管生成蛋白的分布。结果该模型预测，玻璃体内给药的分子在注射后基本上在玻璃体内混合，并且注射药物的长期行为不依赖于最初的混合。不同药物的眼药动学对不同的清除机制敏感。视网膜药物的有效传递受RPE通透性的影响。对于VEGF抗体，玻璃体内注射提供持续的视网膜递送，而SC注射提供更有效，但短时间的小分子视网膜递送。通过皮下注射抗血管生成药物来长期抑制新生血管形成需要频繁注射或持续递送，例如基于微粒的抗血管生成肽递送。结论建立了玻璃体内和皮下注射药物的三维综合模型，为新药和现有药物的给药途径和持续给药装置的测试提供了框架和平台。
Purpose Quantitative understanding of the transport of therapeutic macromolecules following intraocular injections is critical for the design of efficient strategies in treating eye diseases, such as neovascular (wet) age-related macular degeneration (AMD) and macular edema (ME). Antiangiogenic treatments, such as neutralizing antibodies against VEGF or recently characterized antiangiogenic peptides, have shown promise in slowing disease progression. Methods We developed a comprehensive three-dimensional (3D) transport model for intraocular injections using published data on drug distribution in rabbit eyes following intravitreal and suprachoroidal (SC) injection of sodium fluorescein (SF), bevacizumab, and ranibizumab. The model then was applied to evaluate the distribution of small molecules and antiangiogenic proteins following intravitreal and SC injections in human eyes. Results The model predicts that intravitreally administered molecules are substantially mixed within the vitreous following injection, and that the long-term behavior of the injected drug does not depend on the initial mixing. Ocular pharmacokinetics of different drugs is sensitive to different clearance mechanisms. Effective retinal drug delivery is impacted by RPE permeability. For VEGF antibody, intravitreal injection provides sustained delivery to the retina, whereas SC injection provides more efficient, but short-lived, retinal delivery for smaller-sized molecules. Long-term suppression of neovascularization through SC administration of antiangiogenic drugs necessitates frequent injection or sustained delivery, such as microparticle-based delivery of antiangiogenic peptides. Conclusions A comprehensive 3D model for intravitreal and SC drug injection is developed to provide a framework and platform for testing drug delivery routes and sustained delivery devices for new and existing drugs.