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Steven A. Giannos, Edward R. Kraft, Jaafar El-Annan, Mary E. Schmitz-Brown, Valentina Reffatto, Elizabeth Urias, Kevin H. Merkley, Praveena Gupta; Retinal Delivery of Bevacizumab: Anti-aggregation Diluent Eye Drops for Ocular Delivery in Rabbits. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4919.
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Intravitreal injections of anti-VEGF monoclonal antibodies are used to treat wet age-related macular degeneration (AMD) and diabetic retinopathy (DR). An anti-aggregation formula (AAF) enables transscleral permeation of bevacizumab, aflibercept and ranibizumab. This study assessed the in vivo feasibility of delivering bevacizumab to the back of the eye using AAF as the diluent for an eye drop.
Fourteen, New Zealand F1 rabbits - designated Group 1 (bevacizumab in AAF, 5 mg/ml (0.5%)); Group 2 (bevacizumab in PBS, 5 mg/ml (0.5%)) and Vehicle control (AAF). Materials and methods, for the preparation of AAF and PBS were previously described (Giannos et al, Pharm. Res. 2018). Hyaluronic acid (HA) 0.1% was added to AAF, PBS and AAF vehicle control to aid in mucoadhesion. AAF/HA and PBS/HA compositions were sterile filtered prior to addition of 5 mg/ml bevacizumab. AAF vehicle control was absent bevacizumab. Rabbits received an eye drop of approximately 100 µL in each eye, twice daily for 14.5 days, providing a total of 1 mg/day/eye. Aqueous, vitreous, and retina, samples were collected into aliquots containing pre-weighed AAF composition as an assay diluent. Quantitative ELISA was performed to analyze for, and determine the delivered concentration free bevacizumab.
Bevacizumab in AAF permeated and significantly accumulated in the aqueous, vitreous and retina; 10 times or more than when it was diluted in PBS (Table 1). Bevacizumab in AAF/0.1% hyaluronic acid composition with 5 mg/ml bevacizumab, dosed 2 times a day (a clinically relevant dosing schedule) provided higher tissue concentrations in aqueous (1950%), vitreous (100%) and retina (62%) compared to prior work (Nomoto et al. IOVS 2009), using 5 times higher (25 mg/ml) concentrations dosed with a clinically unacceptable schedule (6 times/day).
When diluted in AAF and administered topically, bevacizumab permeated and accumulated in rabbit aqueous, vitreous and retina significantly higher, than when diluted in PBS under the same conditions. Diseased human (AMD & DR), show VEGF from 0.1 to 1.3 ng/ml in the vitreous. Our topical delivery of bevacizumab represents an achievable 1.3x in stoichiometric ratio of drug to VEGF concentration in vitreous for an untreated AMD or DR patient.
This is a 2020 ARVO Annual Meeting abstract.
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