A pharmacodynamic analysis of choroidal neovascularization in a porcine model using three targeted drugs

• Type of Material: Article
• Authors: Jeffrey Tran, Emory University; Caroline Craven, Emory University; Kathy Wabner, Emory University; Jenn Schmit, Emory University; Brock Matter, University of Colorado; Uday Kompella, University of Colorado; Hans Grossniklaus, Emory University; Timothy Olsen, Emory University
• Language: English
• Date: 2017-07-01
• Publisher: Association for Research in Vision and Ophthalmology (ARVO)
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1167/iovs.16-21230
• Title of Journal or Parent Work: Investigative Ophthalmology & Visual Science
• ISSN: 0146-0404
• Volume: 58
• Issue: 9
• Start Page: 3732
• End Page: 3740
• Grant/Funding Information: Supported in part by National Institutes of Health/National Eye Institute RO1 EY022097, P30 EY006360 (Department Core Grant), the Georgia Research Alliance, and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology at Emory University.
• Keywords: Animals; Porcine; Immunoconjugates; Intravitreal Injections; Bevacizumab; Choroidal Neovascularization; Swine; Disease Models, Animal; Vascular Endothelial Growth Factor A; T-Lymphocytes, Cytotoxic; Fluorescein Angiography; Angiogenesis Inhibitors; Sulfonamides; Pyrimidines; Intravitreal drug delivery
• Research Categories: Chemistry, Pharmaceutical; Health Sciences, Opthamology

Abstract

PURPOSE. To compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model. METHODS. Forty-one pigs were injected on the day of CNV induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit μg hI-con1 (n = 4), or 1 mg SC pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for histology. The size of the CNV was determined from histology, and CNV height was the primary outcome measure. Immunostaining for cytotoxic T-cells was performed in the hI-con1 study. RESULTS. In 39 of 41 (95%) eyes, type 2 CNV lesions were identified. One CNV lesion was lost during dissection. One animal was euthanized due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had smaller mean height measurements (90 ± 20 μm) versus controls (180 ± 20 μm; P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 ± 43 μm) compared to SC pazopanib (478 ± 105 μm; P = 0.018). The mean lesion size in hI-con1–treated animals trended smaller than in controls (P = 0.11). Immunostaining did not detect cytotoxic T-cells. CONCLUSIONS. Intravitreal pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig model has nearly a 100% rate of type 2 CNV induction and is a reliable preclinical model with pharmacodynamics similar to humans.