Assessing Delivery Strategies For Non-invasive Administration Of VEGF/PDGF RTK Inhibitors For Ocular Neovascular Disease

Abstract

Purpose: : VEGF/PDGF/c-kit receptor tyrosine kinase inhibitors (RTKI) are being developed for the treatment of ocular neovascular conditions. Two distinct non-invasive strategies were explored as a means of delivery in a model of rodent choroidal neovascularization: uveal melanin-retention following a single oral dose to create a sustained release drug depot, and topical administration.

Methods: : The VEGF/PDGF RTKI and clinical candidate pazopanib has been shown to bind to uveal melanin, thus we created a drug depot by a single oral gavage in mice 3-5 days prior to induction of laser CNV. Reduction in CNV was characterized by fluorescein angiography (FA) and plasma levels of drug were determined at time of CNV induction. A related RTKI with enhanced topical bioavailability, GW771806 was formulated as eye drops and investigated for the ability to regress CNV by FA and immunostaining after BID dosing.

Results: : Pharmacokinetics confirmed that pazopanib cleared systemically prior to induction of CNV and microautoradiography confirmed accumulation in the uvea after a single topical dose. A single oral dose of pazopanib 3-5 days prior to laser injury resulted in a significant (p<0.05) reduction in CNV after laser injury. Eye drop delivery of GW771806 at 5 mg/ml showed a significant regression of CNV lesions whereas 2mg/ml prevented lesion progression. Immunostaining confirmed the regression of CNV and suggested a reduction in pericytes by exposure to GW771806. Combining an intravitreal VEGF neutralizing antibody to the topical RTKI with VEGF/PDGF inhibitory activity increased CNV regression.

Conclusions: : Pazopanib is released from the uveal tract pharmacologically active and reduces laser-induced CNV in mice after a single oral dose, suggesting that melanin retention of drugs could be used as a means to create a sustained release depot. Topical GW771806 regressed CNV, consistent with its enhanced pharmacokinetic profile. The data indicate the feasibility for topical or low dose oral treatment with VEGF/PDGF RTKIs as non-invasive options to treat ocular neovascular disease.

Keywords: age-related macular degeneration • choroid: neovascularization • drug toxicity/drug effects