Assessment Of Intra-ocular Pressure Lowering Effect Of Novel Gel Formulations Of Latanoprost And Timolol In Nonhuman Primates Following Topical Delivery

Abstract

Purpose: : This study was designed to evaluate the ability of novel gel formulations containing latanoprost and timolol to lower intraocular pressure (IOP) in sedated nonhuman primates.

Methods: : Following prescreening to confirm IOP-lowering response to latanoprost, 12 adult African green monkeys were recruited for a multi-week cross-over dosing regimen comprising 4 separate weeks of dosing, on which 4 consecutive days of once-daily topical dosing (50 μl) occurred. Dosing weeks were separated by 10 day washout periods. Dosing sequence was assigned in a Latin square design to 4 treatment groups, based on baseline IOP measures. On study day 1 animals received either gel vehicle, latanoprost 0.0025%/timolol 0.5% gel (formulation 1), Xalacom (latanoprost 0.005%/timolol 0.5%) or latanoprost 0.005%/timolol 0.5% gel (formulation 2) after collecting baseline IOP measures. Follow-up IOP measures were performed immediately prior to and 6 hours after dosing on the first and fourth day of dosing on each study week. Statistical analyses were conducted on absolute IOP values. Studies were conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Results: : Administration of Xalacom resulted in significant IOP lowering at 6 hours after dosing on day 1 of dosing (2.0 mmHg; p<0.0001) compared with response to vehicle treatment in the same animals (0.2 mmHg). Administration of either gel formulation also resulted in significant IOP lowering (formulation 1=2.9 mmHg, p=0.0054; formulation 2=2.4 mmHg, p=0.0004) compared with vehicle at 6 hours after dosing on day 1. No significant differences were observed between Xalacom and either gel formulation. A similar magnitude of IOP lowering activity was observed 24 hours after administration of the third of 4 daily doses for either gel formulation and for Xalacom, suggesting a sustained IOP lowering effect. No further significant IOP lowering was observed at 6 hours after administration of the fourth daily dose.

Conclusions: : The gel formulations tested demonstrated similar IOP lowering activity to Xalacom in a nonhuman primate model. Results suggest the gel formulations may facilitate delivery and provide effective and sustained IOP lowering activity at a lower latanoprost strength, meriting further study.

Keywords: intraocular pressure