Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Opthalmologicals, Anti-inflammatory agents, non-steroids, ATC code: S01BC10

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 NEVANAC 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.
Three pivotal studies were conducted to assess the efficacy and safety of NEVANAC dosed 3 times daily as compared to vehicle and/or ketorolac trometamol in the prevention and treatment of postoperative pain and inflammation in patients undergoing cataract surgery. In these studies, study medication was initiated the day prior to surgery, continued on the day of surgery and for up to 2-4 weeks of the postoperative period. Additionally, nearly all patients received prophylactic treatment with antibiotics, according to clinical practice at each of the clinical trial sites.

In two double-masked, randomised vehicle-controlled studies, patients treated with NEVANAC had significantly less inflammation (aqueous cells and flare) in the early postoperative period through the end of treatment than those treated with its vehicle.


In one double-masked, randomised, vehicle and active-controlled study, patients treated with NEVANAC had significantly less inflammation than those treated with vehicle. Additionally, NEVANAC was non-inferior to ketorolac 5 mg/ml in reducing inflammation and ocular pain, and was slightly more comfortable upon instillation.

A significantly higher percentage of patients in the NEVANAC group reported no ocular pain following cataract surgery compared to those in the vehicle group.

Reduction in the risk of postoperative macular oedema associated with cataract surgery in diabetic patients.
Four studies (two in diabetic patients and two in non-diabetic patients) were conducted to assess the efficacy and safety of NEVANAC for the prevention of postoperative macular oedema associated with cataract surgery. In these studies, study medication was initiated the day prior to surgery, continued on the day of surgery and for up to 90 days of the postoperative period.

In 1 double-masked, randomised vehicle-controlled study, conducted in diabetic retinopathy patients, a significantly greater percentage of patients in the vehicle group developed macular oedema (16.7%) compared to patients treated with NEVANAC (3.2%). A greater percentage of patients treated with vehicle experienced a decrease in BCVA of more than 5 letters from day 7 to day 90 (or early exit) (11.5%) compared with patients treated with Nepafenac (5.6%). More patients treated with NEVANAC achieved a 15 letter improvement in BCVA compared to vehicle patients, 56.8% compared to 41.9%. respectively, p=0.019.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Following 3 times daily dosing of NEVANAC 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 Cmax 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 Cmax.

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 NEVANAC 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.