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Kathleen Krenzer, Sherwin Jiang, Ezra Lowe, Mary Richardson; Comparison of effects between glucocorticoids and mapracorat after repeat topical ocular administration in rabbits for 28 days. Invest. Ophthalmol. Vis. Sci. 2013;54(15):111.
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The purpose of this investigation was to assess the systemic effects of glucocorticoids (GC) as compared to mapracorat, a new selective glucocorticoid receptor agonist (SEGRA) after repeated topical ocular administration for 28 days in rabbits with a 1-week recovery.
The test articles were mapracorat (1, 3, and 6%), Maxidex (dexamethasone sodium phosphate 0.1%), PredForte (prednisolone acetate, 1.0%), and Durezol (difluprednate, 0.05%). The controls were the mapracorat vehicle or saline. Seven NZW rabbits/sex/group were used; 4/sex/group were euthanized after 28 days of dosing and 3/sex/group were euthanized after a 1-week recovery. One eye of each animal was dosed with the respective test article QID (post-operative regimen) and the other eye with the control. In the control group, one eye was dosed with the control and the contralateral eye remained untreated. Animals were periodically assessed for clinical signs, body weight, and ophthalmic findings (including intraocular pressure). At the end of the dosing period, blood samples were collected for toxicokinetic assessment of systemic exposure. Animals were euthanized and blood and tissues collected for clinical chemistry and histopathology assessments.
No adverse ocular effects were observed for any of the test articles. As compared to controls, significant systemic effects were observed in the GC-treated animals, including low body weights and effects on the metabolic/endocrine, cardiovascular, liver, and immune. Partial reversibility was observed after a 1-week recovery period. For the mapracorat-treated groups, no effects were observed with the 1% concentration. For the 3 and 6% groups, no meaningful effects were observed for cardiovascular or liver systems. Dose-related changes were observed for some of the metabolic (low adrenal gland weight) and immune (low thymus weights, low lymphocytes) systems. There was partial (adrenal gland) or full (thymus) reversibility after a 1-week recovery period. When observed, however, the magnitude of the effects was to lesser degree than those observed in the GC-treated animals. No effects were observed with mapracorat that were not within the known effects of GCs.
After 28 days of repeat ocular dosing in rabbits, mapracorat, up to 6%, demonstrates a better systemic safety profile in rabbits than observed with traditional ocular GCs.
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