Nepafenac penetrates most quickly in NSAIDs study

August 1, 2007

In a double-masked, randomized comparison of three leading ocular nonsteroidal anti-inflammatory agents, nepafenac 0.1% (Nevanac, Alcon Laboratories) had significantly greater ocular bioavailability than either ketorolac 0.4% (Acular LS, Allergan) or bromfenac 0.09% (Xibrom, ISTA Pharmaceuticals).

Key Points

"This study provides scientific corroboration of preclinical studies and supports the clinical efficacy of nepafenac when compared with ketorolac or bromfenac," said Dr. Walters, who is in private practice in Austin, TX, as well as medical director at Keystone Clinical Research in that city.

The multicenter, double-masked, randomized, single-dose pharmacokinetic study was designed to determine the aqueous humor concentrations of the three widely used, commercially available topical ophthalmic NSAIDs and amfenac, a nepafenac metabolite.

Enrollment consisted of 75 patients aged 18 years or older who required cataract extraction with planned implantation of an IOL. Patients were randomly assigned to one of five groups and were administered one drop of nepafenac, ketorolac, or bromfenac before cataract surgery. The assigned drug was administered to the different patient subgroups at 30, 60, 120, 180, or 240 minutes preoperatively. Aqueous humor samples were collected from the study eye via preoperative paracentesis; each sample was analyzed for drug concentration, and area under the curve (AUC) at each of five time points was calculated.

The COX-1 and COX-2 inhibitory activities of nepafenac, amfenac, ketorolac, and bromfenac also were determined.

"The results show that nepafenac penetrates more rapidly and significantly greater than any of the other study drugs and is hydrolyzed to its active molecule, amfenac, which steadily increases in anterior chamber concentration up to the 3-hour time point," Dr. Walters said. "That tells us that nepafenac is better at penetrating into the anterior chamber than either of the other two commercially available NSAIDs and then acts as a depot to provide sustained conversion to the active molecule over an extended period."

The study also looked at the COX-1 and COX-2 activity of the two drugs; COX-1 is a protein important to homeostasis, and COX-2 is an inducible enzyme primarily responsible for increased prostaglandin production during ocular inflammation. Results showed that ketorolac had the strongest COX-1 activity, whereas amfenac had the strongest COX-2 activity. This finding demonstrates that the COX-2 inhibition properties of nepafenac are greater than those of ketorolac or bromfenac, Dr. Walters said.

The COX-1 activity of amfenac was similar to that of bromfenac, and the combination of its COX-1 and-2 activities makes it superior to bromfenac or ketorolac, he added.

Researchers also examined the intraocular concentrations of the proinflammatory prostaglandin PGE2. "There was too much noise in these data with no statistically significant difference observed due to the pre-inflammatory condition in this preoperative model," Dr. Walters said.

The lack of significance may stem from the absence of an inflammatory event that would elicit PGE2 reactions to be inhibited, he said. If the analysis were performed after cataract surgery, researchers would be more likely to detect this inflammatory marker, Dr. Walters added.