PT  - JOURNAL ARTICLE
AU  - Joel Proksch
AU  - Ezra Lowe
AU  - Keith Ward
TI  - OCULAR PHARMACOKINETICS OF MAPRACORAT, A NOVEL, SELECTIVE GLUCOCORTICOID RECEPTOR AGONIST, IN RABBITS AND MONKEYS
AID  - 10.1124/dmd.111.039099
DP  - 2011 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.111.039099
4099  - http://dmd.aspetjournals.org/content/early/2011/03/25/dmd.111.039099.short
4100  - http://dmd.aspetjournals.org/content/early/2011/03/25/dmd.111.039099.full
AB  - Mapracorat is a Selective Glucocorticoid Receptor Agonist (SEGRA) in development for the treatment of a variety of ocular diseases. The purpose of this investigation was to evaluate the ocular pharmacokinetics of mapracorat following topical dosing over a range of dose levels in rabbits and monkeys. Mapracorat was administered over a range of doses from 0.01-3000 μg/eye (rabbit) or 50-3000 μg/eye (monkey). All animals received a single instillation, and monkeys also received repeated (3x/day for 4 days) instillations. At predetermined intervals through at least 24 h after dosing, ocular tissues and plasma were collected and analyzed for mapracorat by LC/MS/MS. Mapracorat was rapidly absorbed and widely distributed into ocular tissues after topical ocular administration, with measurable levels sustained through ≥24 h. In both species, mapracorat concentrations were highest in tears followed by conjunctiva and cornea, with lower levels observed in iris/ciliary body and aqueous humor. Mapracorat concentrations in conjunctiva, cornea, and iris/ciliary body increased linearly with increasing dose levels. Ocular exposure was higher following repeated dosing to monkeys when compared with a single dose. Systemic exposure to mapracorat was low following a single administration, with an average Cmax of ≤2.0 ng/mL at the highest dose tested (3000 μg/eye). In comparison with the traditional GCs, dexamethasone (0.1%) and prednisolone acetate (1%), mapracorat (3%) demonstrated similar or higher levels in ocular tissues with lower systemic exposure. The favorable pharmacokinetic profile of mapracorat supports further clinical investigation and suggests that a convenient daily dosing regimen may be efficacious for this novel ophthalmic anti-inflammatory therapy.