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Samirkumar Rajnikant Patel, Rozemarijn S Verhoeven, Brian Burke, Fllorian Cacciamani, Karen Viaud, Henry F Edelhauser; Safety and Tolerability of Drugs Within the Suprachoroidal Space in Albino Rabbits. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4886.
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To evaluate the safety and tolerability of a broad range of injectable drug formulations within the suprachoroidal space in rabbit eyes.
Eleven aqueous drug formulations, 9 suspensions and 2 solutions, were each prepared at 2 different concentrations. Axitinib, sorafenib tosylate, leflunomide, nepafenac, anecortave acetate, azathioprine, dexamethasone acetate, tacrolimus, and mycophenoloic acid were formulated as suspensions. Infliximab (Remicade®), and petoxifylline were formulated as solutions. All formulations were prepared at 10 and 20 mg/mL except for dexamethasone (4 and 8 mg/mL) and anecortave acetate (15 and 30 mg/mL). A single 100 µL suprachoroidal injection of each formulation was administered in the right eye of New Zealand White rabbits. Suprachroidal injections were performed using a 33 G 750 µm length microneedle (Clearside Biomedical Inc, Alpharetta GA). Basic clinical and ophthalmic exams were performed using a McDonald-Shadduck scoring scale pre-injection, and 1, 4, and 7 days post-injection. Injections were performed in four rabbit eyes for each concentration of a given formulation (n=4).
There were no test article or administration related effects on mortality, or animal behavior for all formulations. Only a slight decrease in body weight was observed with the dexamethasone 0.8 mg dose animals (0.1 kg) over the 7-day period. Slight or moderate conjunctival effects (i.e. congestion, swelling and/or discharge) were observed in all groups up to day 1. These effects were likely related to the injection procedure and not to any particular drug or formulation. Axitinib, sorafenib tosylate, leflunomide, nepafenac, infliximab, pentoxifylline, mycophenolic acid, and dexamethasone were well tolerated with only slight-to-moderate ocular effects. Anecortave acetate, azathioprine, and tacrolimus were moderately tolerated with transient ocular effects. One animal for both anecortave acetate and azathioprene displayed mild retinal hemorrhage in the quadrant of the injection site with no signs of pain. Tacrolimus displayed mild transient aqueous inflammation which was not observed after day 4.
Suprachoroidal administration of these eleven compounds was generally safe and tolerable in this one week evaluation period in the rabbit. Most safety and tolerability observations were mild and transient.
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