NSAID activity at trough drug levels

Key Points

Results of a study conducted in an animal model of cataract surgery show that, when measured at a time corresponding to trough drug level, the postoperative aqueous humor concentration of prostaglandin E₂ (PGE₂) was significantly lower in animals treated with ketorolac 0.4% (Acular LS; Allergan) compared with bromfenac 0.09% (Xibrom; ISTA Pharmaceuticals), reported researchers from the Magill Research Center Institute, Medical University of South Carolina, Charleston.

"We believe these findings suggest that when used in commonly practiced perioperative dosing regimens, ketorolac 0.4% may be more effective than bromfenac 0.09% in alleviating inflammation after cataract surgery," said Helga P. Sandoval, MD, MSCR, research assistant professor of ophthalmology, Medical University of South Carolina, Charleston.

The study was presented at the 2008 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). In it, 29 New Zealand white rabbits were randomly arranged into three groups to undergo phacoemulsification in one eye and receive either ketorolac 0.4% four times daily, bromfenac 0.09% twice daily, or BSS. All treatments were started 1 day prior to surgery and were continued postoperatively. There were no significant differences between the three study groups with respect to surgical time or ultrasound time.

"Due to the different dosing schedules of these two NSAIDs, we were interested in assessing their activity at trough levels. The clinical significance of our results in rabbit eyes is unclear, but the findings are consistent with a report presented at last year's ARVO meeting by Amico et al. who found that at trough periods in their respective dosing regimens, b.i.d. dosing of bromfenac 0.09% was less effective than q.i.d. dosing of ketorolac 0.4% in reducing preoperative aqueous PGE₂ levels in patients undergoing cataract surgery," Dr. Sandoval said.

The postoperative evaluations in the rabbit study also included grading of inflammation in masked fashion. There were no significant differences between the two NSAID groups in mean grades for conjunctival/scleral injection, limbal injection, or corneal edema. The percentage of eyes with cells and flare was higher in eyes treated with BSS compared with both ketorolac and bromfenac. In addition, the percentage of eyes with more than 21 cells/mm³ was higher in the bromfenac group compared with the ketorolac group (60% versus 37.5%), although the difference was not statistically significant. Similarly, marked to dense flare was observed in a higher percentage of eyes treated with bromfenac compared with ketorolac (30% versus 0%), although this difference was also not statistically significant.

"Failure to achieve statistical significance in the differences in anterior chamber cell count and flare between the bromfenac and ketorolac groups is likely due to the small sample size in our study. The noted differences in the postoperative examination findings support the idea that the difference between these two drugs in their effects on inhibiting PGE₂ production are likely to be clinically significant," Dr. Sandoval said.

Commenting on the design of the study, Dr. Sandoval said that there have been many clinical studies evaluating the efficacy, safety and pharmacokinetics of different NSAIDs as well as different preclinical investigations where inflammation is induced experimentally with bacterial lipopolysaccharide endotoxin. However, because the clinical studies sample aqueous humor during surgery, they do not give relevant information about the efficacy of the NSAID in controlling the surgically induced inflammatory reaction.

"Although performed in rabbits, our model was designed to have clinical relevance because we measured NSAID control of the inflammatory response after lens extraction by phacoemulsification," Dr. Sandoval said.