Pharmacology: Pharmacodynamics: Mechanism of action: Nepafenac (Nevanac) Sterile Ophthalmic Suspension contains nepafenac (0.1%), a non-steroidal anti-inflammatory and analgesic prodrug. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, a non-steroidal anti-inflammatory drug.
Amfenac is thought to inhibit action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.
Clinical Studies: In two double-masked, randomized clinical trials in which patients were dose three times daily beginning one day prior to cataract surgery, continued on the day of the surgery and for the first two weeks of the postoperative period, nepafenac (Nevanac) Sterile Ophthalmic Suspension demonstrated clinical efficacy, compared to its vehicle in treating postoperative inflammation.
Patient treated with nepafenac (Nevanac) Sterile Ophthalmic Suspension were less likely to have ocular pain and measurable signs of inflammation (cells and flare) in the early postoperative period through the end of treatment than those treated with its vehicle.
For ocular pain, in both studies, a significantly higher percentage of patients (approximately 80%) in the nepafenac group reported no ocular pain on the day following cataract surgery (Day 1) compared to those in the vehicle group (approximately 50%).
Results from clinical studies indicated that nepafenac (Nevanac) Sterile Ophthalmic Suspension has no significant effect upon intraocular pressure; however, changes in intraocular pressure may occur following cataract surgery.
Pharmacokinetics: Absorption: Following 3-time daily dosing of nepafenac 0.1% Eye Drops in both eyes for four days, maximal steady-state plasma concentrations (Cmax) of nepafenac (0.310 + 0.104 ng/mL) and amfenac (0.422 + 0.121 ng/mL) were attained within 0.5 hours. Steady-state plasma levels were achieved by day 2. Based on the steady-state/single dose ration of individual Cmax values, the mean accumulation index was 1.34 + 0.58 for nepafenac and 1.61 + 0.66 for amfenac.
Distribution: Nepafenac and amfenac distributed to ocular tissues in rabbits after single topical dose with either 0.1% or 0.3% suspension. Higher concentrations were observed as site of dosing, cornea and conjunctiva and lower concentrations in posterior tissues, retina and choroid. Concentrations in ocular tissues increased with increased dose. When anterior ocular tissues concentrations were compared from a single dose of 0.3% nepafenac to that after three doses of 0.1% nepafenac in a single day, only the lens did not have a higher concentrations after the 0.3% nepafenac once a day dosing.
In cataract surgical patients, maximal aqueous humor concentrations were observed 1 hour following single dose 0f 0.1% nepafenac with a concentration 177 ng/mL and 44.8 ng/mL for nepafenac and amfenac, respectively.
Plasma protein binding of nepafenac is moderate, ranging from 72.8% in rat plasma to 83.5% in human plasma. Protein binding was found to be concentration independent in rat, monkey and human plasma over a wide concentration range (10 to 1000 ng/mL). Amfenac is more highly bound at approximately 99%.
Biotransformation: Nepafenac undergoes relatively rapid in vivo hydrolysis to amfenac. After oral administration, unconjugated amfenac and nepafenac, and eight other metabolites were detected in plasma with amfenac, a pharmacological active metabolite having the highest concentration. Several of the metabolites were glucuronide conjugates based chromatographic shift after β-glucuronidase treatment. Nepafenac was detected in plasma but at relatively low levels (3.2% of total radioactivity). Amfenac was the major metabolite in plasma, representing approximately 13% of total plasma radioactivity. The second most abundant plasma metabolite was 5-hydroxy nepafenac in the form of a glucuronide, representing approximately 9.5% of total radioactivity at Cmax.
Neither nepafenac nor amfenac inhibit any of the major human cytochrome P-450 isozymes (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) in vitro at concentrations up to 3000 and 1000 ng/mL, respectively.
After 14 days of oral administration, nepafenac does not increase CYP1A, CYP2B, CYP3A activities or total P450 content in rats, therefore, no potential induction was observed for rats.
Elimination: After oral administration of 14C-nepafenac to healthy human volunteers, urinary excretion was found to be the major route of excreted radioactivity, accounting for approximately 85%, while fecal represented approximately 6% of the dose out to 7 days.
Drug-Drug Interaction: Nepafenac at concentrations up to 300 ng/mL did not inhibit the in vitro metabolism of 6 specific marker substrates of cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4).
Therefore, drug-drug interactions involving CYP-mediated metabolism of concomitantly administered drugs are unlikely. Drug-drug interactions mediated by protein binding are also unlikely.
Gender: Data in healthy subjects indicate no clinically relevant or significant gender difference in the steady-state pharmacokinetics of amfenac following three times daily dosing of nepafenac (Nevanac) Sterile Ophthalmic Suspension.
Low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects 2 and 3 hours post-dose, respectively, following bilateral topical ocular TID dosing of nepafenac ophthalmic suspension, 0.1%.
The mean steady-state Cmax for nepafenac and amfenac were 0.310 ± 0.104 ng/mL and 0.422 ± 0.121 ng/mL, respectively, following ocular administration.