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Casey Kopczynski, Gary D. Novack, Dennis Swearingen, Thomas J. Van Haarlem; Ocular Hypotensive Efficacy, Safety, and Systemic Absorption of AR-12286 in Normal Volunteers. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6689.
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To evaluate the ocular hypotensive efficacy, safety and systemic absorption of 0.5% AR-12286 Ophthalmic Solution in normal subjects. AR-12286 is a selective Rho kinase inhibitor that lowers intraocular pressure (IOP) by increasing trabecular outflow.
The trial was a double-masked, single-center, crossover study comparing two formulations of 0.5% AR-12286. Subjects (n=18) were randomized to receive 1 of 2 formulations dosed q.d. AM for 8 days. Subjects underwent a minimum 7-day inter-period washout, and then received the alternate treatment for 8 days. IOP was measured at -30 min (pre-dose), 4 hrs, and 8 hrs on day 0 (baseline), day 1 and day 8. Blood samples were obtained pre-dose and 0.25, 0.5, 1, 2, 4, and 8 hrs post-dose to evaluate the systemic exposure to AR-12286 on day 1 and day 8.
Both formulations of AR-12286 produced substantial reductions from baseline IOP that were statistically significant (p < 0.0001) at all post-dose time points. Baseline mean IOP at -30 min, 4 hrs and 8 hrs was 17.0, 16.5 and 15.9 mm Hg, respectively. On day 8 of treatment, mean IOP was reduced to 13.6 (-3.4), 9.6 (-6.9) and 11.9 (-4.0) mm Hg, respectively (all results for formulation CF286-04). Reduction in mean IOP was 41% at peak (4 hrs) and 18% at trough (24 hrs). Systemic exposure to AR-12286 was very low; only 5 of 18 subjects had plasma concentrations above 1 ng/mL at any time point (lower limit of quantitation). The only adverse event of note was trace to moderate conjunctival hyperemia that gradually returned to baseline by 8 hrs after dosing.
AR-12286 0.5% dosed q.d. AM reduced IOP by 18 - 41% in normotensive volunteers. Previous studies of prostaglandin analogues in normotensive subjects have reported IOP reductions of 14 - 25%. Further evaluation of AR-12286 in the treatment of low pressure glaucoma is warranted.
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