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Irach B. Taraporewala, Michael J. Elman, Shalom Z. Hirschman, Samuel I. Backenroth; A Novel Eye Drop Formulation of Squalamine For Exudative AMD: Evaluation Of Ocular Distribution And Ocular Safety In Rabbits. Invest. Ophthalmol. Vis. Sci. 2012;53(14):457.
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To evaluate the ocular safety and ocular tissue distribution of a novel eye drop formulation of Squalamine, a potent antiangiogenic small molecule inhibitor of multiple growth factors (VEGF, PDGF, bFGF) with previously demonstrated systemic activity in vivo in ocular pathologies and in clinical trials for exudative macular degeneration.
Male Dutch belted rabbits (n=24) were administered Squalamine eye drops bilaterally, either QD (every 24 hours) or BID (every 12 hours) for 1, 7, and 14 days (n=4/group/dose). Ocular tissues were harvested 24 (±2) or 12(±1) hours post last dosing in the QD or BID groups, respectively. Posterior sclera/choroid, aqueous and vitreous humors, and plasma were assayed for Squalamine concentrations using a validated LC-MS/MS method with a lower limit of quantification (LLOQ) of 10ng/g of tissue. Ocular toxicity and irritation were also evaluated.
Squalamine eye drops, given QD or BID were well tolerated with no adverse clinical effects. Given QD, mean concentrations of Squalamine inposterior sclera/choroid were 9.5, 21.9, and 39.8ng/g in the 1, 7, and 14 daygroups, respectively. Given BID, mean concentrations of Squalamine in posterior sclera/choroid were 21.7, 62.6, and 68ng/g in the 1, 7, and 14 day groups, respectively. Values represent levels at one full dosing interval after last administration (QD 24(+2) hours, BID 12(+1) hours). Squalamine concentrations in aqueous and vitreous humors were <LLOQ in all animals and <LLOQ in plasma in 23/24 animals.
Squalamine eye drops were well tolerated, consistent with previous longer term preclinical studies in which there were no adverse clinical findings or changes in ocular histopathology. Mean posterior segment tissue concentrations of Squalamine given QD and BID exceeded the threshold at which Squalamine is known to inhibit neovascularization in a cell-based model. Importantly, as evidenced by concentrations in posterior sclera/choroid above the anti-angiogenic threshold level, sustained therapeutically relevant posterior ocular exposure levels were maintained for the duration of a full dosing interval (QD 24h, BID 12h). Squalamine has prolonged residence time and slow tissue clearance when administered QD and BID up to 14 days. Minimal systemic uptake reduces potential systemic safety concerns. The absence of Squalamine concentrations in aqueous humor suggests a passive diffusion mechanism from anterior to posterior sclera and subsequently into the choroid. These results, consonant with previous preclinical topical data and intravenous clinical studies, warrant further clinical investigation of Squalamine eye drops to treat neovascular ophthalmic disorders.
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