Ocular Pharmacokinetics of Mapracorat, a Novel, Selective Glucocorticoid Receptor Agonist, in Rabbits and Monkeys

• Published in: Drug metabolism and disposition Vol. 39; no. 7; pp. 1181 - 1187
• Main Authors: PROKSCH, Joel W, LOWE, Ezra R, WARD, Keith W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.07.2011
• Subjects: Animals; Benzofurans - pharmacokinetics; Biological and medical sciences; Chromatography, Liquid; Dexamethasone - pharmacokinetics; Dose-Response Relationship, Drug; Eye - metabolism; Female; Macaca fascicularis; Male; Medical sciences; Pentanols - pharmacokinetics; Pharmacology. Drug treatments; Prednisolone - pharmacokinetics; Quinolines - pharmacokinetics; Rabbits; Receptors, Glucocorticoid - agonists; Tandem Mass Spectrometry; Agonist; Antiinflammatory agent; Monkey; Rabbit; Lagomorpha; Eye; Visual system; Vertebrata; Mapracorat; Mammalia; Animal; Glucocorticoid receptor; Primates; Pharmacokinetics; Hormonal receptor
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.111.039099

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.