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Scott J. Robbie, Peter Lundh von Leithner, Meihua Ju, Peter S. Adamson, Pete Coffey, Yin-Shan Ng, James W. Bainbridge, David T. Shima; Assessing Delivery Strategies For Non-invasive Administration Of VEGF/PDGF RTK Inhibitors For Ocular Neovascular Disease. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4892.
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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.
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.
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.
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.
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