Aqueous Humor Penetration of Ketorolac Formulated in DuraSite or DuraSite 2 Delivery Systems Compared to Acular LS in Rabbits

Abstract

Abstract

Purpose:

To evaluate the ocular penetration of ISV-304 (ketorolac tromethamine) formulated in DuraSite^® or DuraSite^® 2 compared to Acular LS^® (0.4% ketorolac ophthalmic solution) in rabbits.

Methods:

The left eye of rabbits received a single topical instillation of either ISV-304 (0.2% and 0.4% ketorolac) in DuraSite, ISV-304 (0.2% and 0.4% ketorolac) in DuraSite 2, or Acular LS. At predetermined time points, aqueous humor (AH) levels of ketorolac were measured by HPLC-MS/MS, and C_max, T_max, and AUC_0.25–24h were determined.

Results:

The highest mean concentration of ketorolac was achieved in ISV-304 (0.4%) formulated in DuraSite 2 with a C_max value of 1889±884 ng/mL, compared to C_max values for ISV-304 (0.4%) formulated in DuraSite (1212±435 ng/mL) or Acular LS (275±83 ng/mL). ISV-304 (0.2%) formulations also achieved higher AH C_max values (801±205 ng/mL and 1077±415 ng/mL) compared to Acular LS. There was a significant increase in drug exposure in the ISV-304 (0.4%) formulated in DuraSite 2 or DuraSite formulations with AUC_0.25–24h values 6836 ng/mL*h and 5684 ng/mL*h, respectively, compared to Acular LS with an AUC_0.25–24h value of 1424 ng/mL*h. ISV-304 (0.2%) formulations also had high AUC_0.25–24h values (3241 ng/mL*h and 4490 ng/mL*h), which were a 2.3-3.2-fold increase over the Acular LS AUC_0.25–24h value.

Conclusions:

DuraSite and DuraSite 2 delivery systems markedly improved the ketorolac ocular pharmacokinetic parameters in rabbits. DuraSite formulations may lessen the side effects associated with topical nonsteroidal anti-inflammatory drug use by maintaining efficacy with a reduced dosing regimen and reduced active ingredient.