Optanep Mechanism of Action

Pharmacotherapeutic group: Non-steroidal Anti-inflammatory agents.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Clinical efficacy and safety: Prevention and treatment of postoperative pain and inflammation associated with cataract surgery: The efficacy and safety of nepafenac in the prevention and treatment of postoperative pain and inflammation associated with cataract surgery has been demonstrated in two masked, double-blind, placebo-controlled clinical trials in a total of 1351 patients. In this study, patients were dosed daily beginning one day prior to cataract surgery, continued on the day of surgery, and for the first 14 days of the postoperative period. Nepafenac 3 mg/mL eye drops, suspension demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation.
Patients treated with Nepafenac were less likely to have ocular pain and measurable signs of inflammation in the early postoperative period through to the end of treatment than those treated with its vehicle. In the two studies, Nepafenac cleared inflammation at day 14 post-operation in 65% and 68% of patients compared to 25% and 35% of patients on a vehicle. Pain-free rates in the Nepafenac group were 89% and 91% compared to 40% and 50% of patients on vehicles. Some patients received nepafenac 3 mg/mL eye drops, suspension for up to 21 days post operation. However, efficacy beyond day 14 post operation was not measured.
In addition, in one of the two clinical trials, nepafenac 3 mg/mL eye drops, suspension dosed once a day showed a similar effect with nepafenac 1 mg/mL eye drops, suspension dosed three times a day for the prevention and treatment of postoperative pain and inflammation following cataract surgery. Inflammation clearing and pain-free rates were similar for both products at all postoperative evaluations.
Pharmacokinetics: General Properties: Absorption: Following one drop of nepafenac 3 mg/mL eye drops, in both eyes once daily for four days, 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 was 0.847 ± 0.269 ng/mL and 1.13 ± 0.491 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 radioactively labeled active substance-related materials distribute widely in the body following single and multiple oral doses of 14C-nepafenac.
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 fecal excretion represented approximately 6% of the dose.
Toxicology: Preclinical safety data: 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 post implantation loss, reduced fetal weights and growth, and reduced fetal 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.