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Philippe Daull, Grégory Lambert, Laura Rabinovich, Jean-Sébastien Garrigue, Baruch D. Kuppermann; Efficacy and Ocular Tissues Distribution of Dexamethasone Following a Single Intravitreal Injection of Oil-in-Water Emulsion of Prodrug Dexamethasone Palmitate in Pigmented Rabbits. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1698.
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The goal of this study was to characterize the sustained release capacity of an oil-in-water emulsion of the prodrug dexamethasone palmitate (DXP), and the ocular tissue distribution of dexamethasone (DXM), following a single intravitreal injection in rabbit eyes. The retina and choroid DXM and DXP concentrations were paralleled with the efficacy of the drug at reducing VEGF-induced vascular hyperpermeability.
Pigmented rabbits (n=6 per group) received a single unilateral intravitreous (IVT) injection of oil-in-water emulsions of DXP at strengths ranging from 0.8 to 3.2%. DXP was dosed at 100, 200, 400, and 1280 µg by an IVT of 12.5, 25, 50, or 40 µl, respectively. The aqueous humor, vitreous, retina and choroid were harvested at time points 1, 4, 8, 16, 24, 32, and 36 weeks post IVT injection. The long term efficacy was assessed at time points 16, 24, 36 weeks, as by VEGF challenge, assessed by IVT injection of rhVEGF165 (500 ng) 2 days before an IV injection of fluorescein. Fluorontron measurements were performed 1h after the fluorescein injection.
The PK data demonstrated that DXP is converted in DXM, which was present at therapeutic doses in the retina and choroid until 9 months at the higher dose; 1179.6 and 577.7 ng/g, respectively. DXM’s half life in the retina and choroid was 189 and 103 days, respectively. DXP was still present in the target tissues at the end of the experimental period, and served as a ‘reservoir’ for DXM. At the lower doses (400 µg) DXM was present at therapeutic doses in the choroid until month 2 (691.6 ng/g). VEGF challenges confirmed that the highest dose was able to reduced VEGF-induced hyperpermeability until month 9 (Rt = 1.07).
The data demonstrated that the oil-in-water emulsion is an effective delivery system for the prodrug DXP, the latter acting as a ‘reservoir’ for DXM. Long term efficacy was obtained following a single IVT injection for doses as low as 400 µg DXP in the rabbit.
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