ISER 2010 - Session Planner

TOPICAL AND INTRAVITREAL PHARMACOKINETICS OF THE ANTI-ANGIOGENIC AGENT, OC-10X, IN THE RAT

A. Hosseini, F.A. Lattanzio, Jr, P.B. Williams

T. R. Lee Center for Ocular Pharmacology, Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA

Background and aims: Exudative age-related macular degeneration (AMD) is a common debilitating eye disease characterized by the growth of abnormal, fragile blood vessels under the retina (choroidal neovascularization, CNV) leading to legal blindness. Current therapies for exudative AMD and CNV include multiple intravitreal injections of vascular endothelial growth factor inhibitors with or without laser photocoagulation. Intravitreal injections pose problems in terms of patient compliance and the potential for ocular damage that topical drug administration would circumvent. OC-10X is a novel anti-angiogenic agent that represents a unique and first in class AMD treatment. This study compares the pharmacokinetics of topical and intravitreal ¹⁴C-radiolabeled OC-10X in the rat.
Methods: Both eyes of 12 Sprague-Dawley (SD) rats were topically treated thrice daily (20 µl 1% ¹⁴C-OC-10X). Groups of 4 treated rats were then euthanized 1 hour following the morning dose after 1, 4, 7 or 14 days of treatment. In a second experiment, both eyes of 24 SD rats received a single intravitreal 2 µl injection of 1% ¹⁴C-OC-10X, with groups of 6 treated rats euthanized after 1, 4, 7 or 14 days. All animals were monitored for ocular or systemic adverse effects. After euthanasia, tissue samples were collected, weighed and prepared for ¹⁴C scintillation counting.
Results: Bilateral topical OC-10X administration resulted in stable, salient concentrations (1.126 ± 1.08 µg/g) in the target tissue, retina which were maintained from the 4^th to 14^th day without any adverse effects. In comparison, the initial retinal concentration of OC-10X was much higher at the 1^st day after intravitreal injection (17.733 ± 18.703 µg/g), but it dropped to 10 times less than the topical application within 4 days (0.18 ± 0.26 µg/g) and continued to fall over 14 days (0.004 ± 0.014 µg/g). The concentration in plasma (0.003 to 0.066 µg/ml) and accumulation in major organs (range from 0.001 in brain to 0.033 µg/g in gut) were much lower than the accumulation in retina.
Conclusion: To maintain rat retinal OC-10X concentrations comparable to that of topical treatment would require multiple intravitreal injections. This retinal concentration sustained after topical administration is comparable to IC-50 in bovine retinal endothelial cell proliferation in vitro. Our other studies have shown that in a rat CNV model the topical OC-10X regimen significantly reduced CNV (up to 41% less CNV than vehicle treated controls), demonstrating that intravitreal administration is not necessary to safely and effectively treat CNV.