title: Ocular pharmacokinetics of mapracorat, a novel, selective glucocorticoid receptor agonist, in rabbits and monkeys.
abstract: Mapracorat is a selective glucocorticoid receptor agonist in development for the treatment of a variety of ocular diseases. The purpose of this investigation was to evaluate the ocular pharmacokinetics of mapracorat after topical dosing over a range of dose levels in rabbits and monkeys. Mapracorat was administered over a range of doses from 0.01 to 3000 μg/eye (rabbit) or 50 to 3000 μg/eye (monkey). All animals received a single instillation, and monkeys also received repeated (three times per 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 liquid chromatography-tandem mass spectrometry. 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 after repeated dosing to monkeys than after a single dose. Systemic exposure to mapracorat was low after a single administration, with an average maximal concentration of ≤2.0 ng/ml at the highest dose tested (3000 μg/eye). In comparison with the traditional glucocorticoids, 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.
authors: Pharmaceutical Research and Development, Bausch & Lomb, Inc., Rochester, NY 14609, USA. joel_w_proksch@bausch.com
authors: Joel W
authors: JW
authors: Proksch
authors: Ezra R
authors: ER
authors: Lowe
authors: Keith W
authors: KW
authors: Ward
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003907:Dexamethasone / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000378:metabolism*; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D000439:Pentanols / Q000493:pharmacokinetics*; D011239:Prednisolone / Q000493:pharmacokinetics; D011804:Quinolines / Q000493:pharmacokinetics*; D011817:Rabbits; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D053719:Tandem Mass Spectrometry
chemical_list: D001572:Benzofurans; D000439:Pentanols; D011804:Quinolines; C546413:R-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(((2-methyl-5-quinolyl)amino)methyl)pentan-2-ol; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D011239:Prednisolone