Ocular Penetration and Pharmacokinetics of Ripasudil Following Topical Administration to Rabbits.

PURPOSE: We evaluated the ocular pharmacokinetics of ripasudil (K-115), a selective Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, following topical administration to rabbits.

METHODS: We determined the ocular distribution of [(14)C]ripasudil by whole-head autoradiography and the radioactivity of each ocular tissue after single and multiple instillation of [(14)C]ripasudil to pigmented rabbits. We also measured the aqueous humor concentrations after concomitant instillation of ripasudil and a combination agent (0.005% latanoprost and 0.5% timolol) to pigmented rabbits as well as the tear fluid concentrations after instillation into rabbits, dogs, and monkeys using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Membrane permeability was evaluated using an in vitro parallel artificial membrane permeability assay system and Ussing chamber with rabbit cornea and conjunctiva.

RESULTS: [(14)C]Ripasudil was rapidly absorbed into the cornea and distributed throughout the eye after topical instillation. The melanin-containing ocular tissues, such as the iris-ciliary body and retina-choroid, showed much higher concentrations of radioactivity than the other nonpigmented tissues. Concomitant instillation showed minor effects on the aqueous humor concentrations of each compound in rabbits. Membrane permeability of ripasudil was higher than other glaucoma drugs in vitro and ex vivo. The aqueous humor concentrations of ripasudil in rabbits were higher than those in dogs and monkeys in the early period after instillation and associated with tear turnover rate.

CONCLUSIONS: These results indicate favorable intraocular penetration characteristics of ripasudil following topical administration.