title: Aqueous humor penetration of ketorolac formulated in DuraSite or DuraSite 2 delivery systems compared to Acular LS in rabbits.
abstract: OBJECTIVE
  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 Cmax, Tmax, and AUC0.25-24h were determined.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: 1 Department of Preclinical Research and Development, InSite Vision, Alameda, California.
authors.forename: Afshin
authors.initials: A
authors.lastname: Shafiee
authors.forename: Lyle M
authors.initials: LM
authors.lastname: Bowman
authors.forename: Eddie
authors.initials: E
authors.lastname: Hou
authors.forename: Kamran
authors.initials: K
authors.lastname: Hosseini
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D005260:Female; D020911:Ketorolac Tromethamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D011817:Rabbits; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020911:Ketorolac Tromethamine