A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model Using Three Targeted Drugs.

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.

• Authors: Jeffrey Tran, Caroline Craven, Kathy Wabner, Jenn Schmit, Brock Matter, Uday Kompella, Hans E Grossniklaus, Timothy W Olsen
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 58 Issue 9 Pg. 3732-3740 (07 01 2017) ISSN: 1552-5783 [Electronic] United States
• PMID: 28738417 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Immunoconjugates
• Indazoles
• Pyrimidines
• Sulfonamides
• Vascular Endothelial Growth Factor A
• hI-con1
• Bevacizumab
• pazopanib

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Bevacizumab (pharmacology)
• Choroidal Neovascularization (drug therapy, pathology)
• Disease Models, Animal
• Fluorescein Angiography
• Immunoconjugates (pharmacology)
• Indazoles
• Intravitreal Injections
• Pyrimidines (pharmacology)
• Sulfonamides (pharmacology)
• Swine
• T-Lymphocytes, Cytotoxic (immunology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)