Abstract
Purpose: :
Inhibitors of Rho kinase have emerged as a new class of potential glaucoma medication and are currently being tested in the clinic. Since many of these molecules have suffered from poor duration of action and ocular irritation, we sought to develop kinase inhibitors with greater hypotensive efficacy and improved tolerability.
Methods: :
The effect of AR-12286 on IOP and its duration of effect with once-daily dosing were characterized in normotensive Dutch Belted rabbits (DB) rabbits and in normotensive cynomolgus monkeys. Test formulations were administered to one eye with the untreated eye serving as a control. AR-12286 activity was compared directly toY-39983, a Rho kinase inhibitor currently in clinical development. The ocular tolerability of AR-12286 solutions (0.3%, 0.6%,1%) was evaluated in female New Zealand White (NZW) rabbits dosed eight times daily,1 hour apart, for seven consecutive days.
Results: :
AR-12286 and Y-39983 formulations produced statistically significant (p < 0.05) reductions in IOP (ΔIOP) with once-daily dosing in DB rabbits. AR-12286 at 0.3% produced a larger ΔIOP at all time points relative to 0.3% Y-39983. 0.3% AR-12286 elicited a maximum ΔIOP of 6.6 mmHg and exhibited a longer duration of effect at 8 hours (ΔIOP 2.0 mmHg) compared to 0.3% Y-39983. Increasing AR-12286 to 0.6% and 1.0% resulted in dose-dependent increases in ΔIOP with no sign of ocular irritation. Similar IOP lowering and tolerability were observed in monkeys, with AR-12286 achieving a larger maximal ΔIOP (~5 mmHg) and longer duration of effect than Y-39983. In the NZW rabbit ocular tolerability study, exaggerated dosing of AR-12286 at concentrations of 0.3%, 0.6% or 1% eight times daily for seven days produced only mild conjunctival and iridial hyperemia that was slightly greater than AR-12286 vehicle.
Conclusions: :
Rabbit and monkey studies demonstrate that AR-12286 produces large reductions in IOP with a longer duration of action than the previously characterized Rho kinase inhibitor Y-39983. AR-12286 produced no ocular irritation when dosed once-daily and produced only slight conjunctival and iridial hyperemia when dosed eight times daily for 7 days
Keywords: intraocular pressure • signal transduction: pharmacology/physiology