Prodrug is target-specific therapy for cataracts

Nepafenac is a prodrug of the potent nonsteroidal anti-inflammatory drug (NSAID) amfenac. Animal studies demonstrate that after topical administration, nepafenac penetrates rapidly into the cornea and is well distributed to the retina, choroid, iris, and ciliary body where it undergoes bioactivation by hydrolase enzymes to amfenac. Excellent bioavailability at target tissues accounts for the impressive efficacy demonstrated by nepafenac in clinical trials in terms of reducing pain and anterior segment inflammation after cataract surgery and also confers on it the important potential for minimizing the risk of postoperative cystoid macular edema (CME), said Dr. Leh-mann, who spoke at the Alcon booth in the technical exhibit hall as part of the Alcon Speaker's Forum program.

Rapid postop recovery

While current perioperative medication regimens using a topical corticosteroid combined with a conventional NSAID have been highly effective in reducing the risk of CME, Dr. Lehmann noted his belief that low-grade CME may be more common than currently appreciated. As such, it may be an underlying, but unrecognized cause in patients who achieve good uncorrected visual acuity after lens removal surgery but still present with complaints about suboptimal quality of vision.

"Results of an animal study demonstrated nepafenac was superior to other NSAIDs [diclofenac 0.1% (Voltaren, Novartis Pharmaceuticals) and ketorolac 0.5% (Acular, Allergan)] for preventing experimentally-induced retinal edema, inhibiting blood-retinal-barrier breakdown, and suppressing posterior segment prostaglandin synthesis," Dr. Lehmann said. "Therefore, I believe that nepafenac is likely a tremendous tool for reducing the occurrence of CME after lens removal surgery. It is an important addition for optimizing outcomes of all patients undergoing cataract surgery and especially those receiving presbyopia-correcting lenses after cataract or clear lens removal."

Dr. Lehmann was an investigator in one of the phase III clinical trials that led to the FDA approval of nepafenac for treating pain and inflammation after cataract surgery. Based on that experience, he now uses this new agent as his NSAID of choice for patients undergoing lens removal surgery. Treatment is initiated on the day before surgery and continued for 3 weeks using the recommended three-times-daily dose. His medication regimen also includes a topical fourth-generation fluoroquinolone and a topical corticosteroid.

"NSAIDs and steroids work via two different-but-complementary mechanisms to reduce synthesis of pro-inflammatory prostaglandins. Therefore, these agents should always be used in combination to maximize control of inflammation and reduce the risk of CME after surgery," Dr. Lehmann said.

In premarketing clinical trials, nepafenac was investigated as monotherapy to establish its efficacy in controlling pain and inflammation. In one study, 476 patients were randomly assigned 1:1 to t.i.d. treatment with vehicle or nepafenac starting on the day before surgery and continuing for 14 days postoperatively with an additional dose given just prior to surgery. At assessments performed on days 1, 3, 7, and 14 after surgery, patients in the nepafenac group consistently had significantly less ocular pain and inflammation compared with the controls.