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Janet Tully, Stuart Williams, Dustin Melton, RiLee Robeson, Mari Yang, Rozemarijn Verhoeven; AR-1105 Dexamethasone Extended Release and Pharmacokinetics in the Non-Human Primate. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5673.
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Intravitreal dexamethasone is used in the treatment of diabetic macular edema (DME), retinal vein occlusion (RVO), and uveitis. An extended release biodegradable IVT implant with a dose sparing, linear release rate has the potential for an improved safety profile and extended duration of effect compared with marketed products. Here we demonstrate the ability to fabricate biodegradable, dexamethasone-containing IVT implants that provide extended release of dexamethasone in the monkey for at least six months.
AR-1105 was designed for intravitreal delivery of extended release dexamethasone using the PRINT technology. Drug content and in vitro release were measured by RP-HPLC. In vitro release rates were measured at 37C in 1X PBS, pH 7.4 with 0.1% Triton X-100. Pharmacokinetics and tolerability of AR-1105 was evaluated in the cynomolgous monkey for up to six months post-dose. Ophthalmic exams and intraocular pressure (IOP) measurements were conducted, and ocular matrices, remaining implants, and plasma were processed and analyzed by LC-MS/MS at terminal time points.
In vitro release of dexamethasone was demonstrated for up to six months. In the monkey, dexamethasone exposure was demonstrated for at least six months. Therapeutically relevant dexamethasone concentrations were present in target tissues of retina, choroid, and vitreous at all time points studied, while anterior chamber and systemic exposure was minimal. There was no test article-related effect on IOP.
AR-1105 provided extended release of dexamethasone from biodegradeable, intravitreal implants in vitro and in the monkey through six months, and was well tolerated. Intravitreal administration of a dose sparing dexamethasone implant resulted in drug delivery to the posterior target tissues with minimal anterior chamber or systemic exposure and excellent ocular tolerability, and may thus decrease the risk of adverse effects.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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