Aqueous humor penetration of ketorolac formulated in DuraSite or DuraSite 2 delivery systems compared to Acular LS in rabbits

• Published in: Journal of ocular pharmacology and therapeutics Vol. 29; no. 9; p. 812
• Main Authors: Shafiee, Afshin, Bowman, Lyle M, Hou, Eddie, Hosseini, Kamran
• Format: Journal Article
• Language: English
• Published: United States 01.11.2013
• Subjects: Administration, Ophthalmic; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Aqueous Humor - metabolism; Area Under Curve; Chromatography, High Pressure Liquid; Drug Delivery Systems; Female; Ketorolac Tromethamine - administration & dosage; Ketorolac Tromethamine - pharmacokinetics; Male; Rabbits; Tandem Mass Spectrometry; Time Factors
• ISSN: 1557-7732
• DOI: 10.1089/jop.2013.0016

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. 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 Cmax, Tmax, and AUC0.25-24h were determined. The highest mean concentration of ketorolac was achieved in ISV-304 (0.4%) formulated in DuraSite 2 with a Cmax value of 1889 ± 884 ng/mL, compared to Cmax 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 Cmax 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 AUC0.25-24h values 6836 ng/mL*h and 5684 ng/mL*h, respectively, compared to Acular LS with an AUC0.25-24h value of 1424 ng/mL*h. ISV-304 (0.2%) formulations also had high AUC0.25-24h values (3241 ng/mL*h and 4490 ng/mL*h), which were a 2.3-3.2-fold increase over the Acular LS AUC0.25-24h value. 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.