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E. R. Lowe, A. K. Chappa, S. Glogowski, J. W. Proksch; Ocular Pharmacokinetics of BOL-303242-X, a Novel Selective Glucocorticoid Receptor Agonist, in Pigmented Rabbits and Cynomolgus Monkeys. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2444.
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© ARVO (1962-2015); The Authors (2016-present)
BOL-303242-X is a novel Selective Glucocorticoid Receptor Agonist (SEGRA) currently of interest for the treatment of a variety of ocular diseases. In vivo studies were designed to investigate the ocular and systemic pharmacokinetics of BOL-303242-X following both single and repeated topical ocular dosing to pigmented rabbits and cynomolgus monkeys.
BOL-303242-X was formulated as a suspension and administered topically to each eye in a dose volume of 35-50 µL over a dose range of 0.01-3000 µg/eye for rabbits and 50-3000 µg/eye for monkeys. At pre-determined time intervals after dosing, the animals were euthanized under anesthesia, tear fluid and plasma collected, and the eyes enucleated and dissected with the collection of ocular tissues. Levels of BOL-303242-X were determined using LC/MS/MS.
Overall, BOL-303242-X was rapidly absorbed into ocular tissues after topical administration with minimal systemic exposure in rabbits and monkeys. BOL-303242-X concentrations were highest in tears, followed by conjunctiva and cornea. Over the wide range of doses studied, BOL-303242-X concentrations in ocular tissues generally increased with increasing dose levels; however, the increase in exposure tended to be less than proportional to the increase in the administered dose in both species. In studies involving repeated administration of BOL-303242-X, ocular exposure tended to be higher following 4x/day dosing in the rabbit and 3x/day dosing in the monkey compared with a single administration. Systemic exposure to BOL-303242-X following topical ocular dosing was measurable, but generally low in both species, with a maximum concentration of 3.41 ng/mL in rabbits and 1.52 ng/mL in monkeys at the highest tested doses. Based on Cmax and AUC values, ocular and systemic exposure to BOL-303242-X in monkeys was comparable with exposure observed at the same dose levels in rabbits.
The promising pharmacokinetic behavior of BOL-303242-X, together with its potent anti-inflammatory and immunomodulatory properties supports the ongoing clinical development of this compound.
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