Nepafenac

Nepafenac is 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 nonsteroidal anti-inflammatory drug. Amfenac inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme required for prostaglandin production.

Secondary pharmacology

In rabbits, nepafenac has been shown to inhibit blood-retinal-barrier breakdown, concomitant with suppression of PGE₂ synthesis. Ex vivo, a single topical ocular dose of nepafenac was shown to inhibit prostaglandin synthesis in the iris/ciliary body (85%-95%) and the retina/choroid (55%) for up to 6 hours and 4 hours, respectively.

Pharmacodynamic effects

The majority of hydrolytic conversion is in the retina/choroid followed by the iris/ciliary body and cornea, consistent with the degree of vascularised tissue.

Results from clinical studies indicate that nepafenac eye drops have no significant effect on intraocular pressure.

Absorption

Following 3 times daily dosing of nepafenac eye drops in both eyes, low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects 2 and 3 hours post-dose, respectively. The mean steady-state plasma C_max for nepafenac and for amfenac were 0.310 ± 0.104 ng/ml and 0.422 ± 0.121 ng/ml, respectively, following ocular administration.

Distribution

Amfenac has a high affinity toward serum albumin proteins. In vitro, the percent bound to rat albumin, human albumin and human serum was 98.4%, 95.4% and 99.1%, respectively.

Studies in rats have shown that radioactive labelled active substance-related materials distribute widely in the body following single and multiple oral doses of ¹⁴C-nepafenac.

Studies in rabbits demonstrated that the topically administered nepafenac is distributed locally from the front of the eye to the posterior segments of the eye (retina and choroid).

Biotransformation

Nepafenac undergoes relatively rapid bioactivation to amfenac via intraocular hydrolases. Subsequently, amfenac undergoes extensive metabolism to more polar metabolites involving hydroxylation of the aromatic ring leading to glucuronide conjugate formation. Radiochromatographic analyses before and after β-glucuronidase hydrolysis indicated that all metabolites were in the form of glucuronide conjugates, with the exception of amfenac. Amfenac was the major metabolite in plasma, representing approximately 13% of total plasma radioactivity. The second most abundant plasma metabolite was identified as 5-hydroxy nepafenac, representing approximately 9% of total radioactivity at C_max.

Interactions with other medicinal products: Neither nepafenac nor amfenac inhibit any of the major human cytochrome P450 (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) metabolic activities in vitro at concentrations up to 3000 ng/ml. Therefore, interactions involving CYP-mediated metabolism of concomitantly administered medicinal products are unlikely. Interactions mediated by protein binding are also unlikely.

Elimination

After oral administration of ¹⁴C-nepafenac to healthy volunteers, urinary excretion was found to be the major route of radioactive excretions, accounting for approximately 85% while faecal excretion represented approximately 6% of the dose. Nepafenac and amfenac were not quantifiable in the urine.

Following a single dose of nepafenac in 25 cataract surgery patients, aqueous humour concentrations were measured at 15, 30, 45 and 60 minutes post-dose. The maximum mean aqueous humour concentrations were observed at the 1 hour time-point (nepafenac 177 ng/ml, amfenac 44.8 ng/ml). These findings indicate rapid corneal penetration.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Nepafenac has not been evaluated in long-term carcinogenicity studies.

In reproduction studies performed with nepafenac in rats, maternally toxic doses ≥10 mg/kg were associated with dystocia, increased postimplantation loss, reduced foetal weights and growth, and reduced foetal survival. In pregnant rabbits, a maternal dose of 30 mg/kg that produced slight toxicity in the mothers showed a statistically significant increase in the incidence of litter malformations.