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Bromfenac

Mechanism of Action

Bromfenac is a non-steroidal anti-inflammatory drug (NSAID) that has anti-inflammatory activity which is thought to be due to its ability to block prostaglandin synthesis by inhibiting primarily cyclooxygenase 2 (COX-2). Cyclooxygenase 1 (COX-1) is only inhibited to a small extent. In vitro, bromfenac inhibited the synthesis of prostaglandins in the rabbit iris ciliary body. The IC50- values were lower for Bromfenac (1.1 μM) than for indometacin (4.2 μM) and pranoprofen (11.9 μM) Bromfenac at concentrations of 0.02%, 0.05%, 0.1% and 0.2% inhibited almost all signs of ocular inflammation in an experimental uveitis model in rabbits.

Pharmacodynamic Properties

Clinical efficacy

Two Phase II multicentre, randomised, double-masked, parallel group studies were conducted in Japan, and two Phase III multicentre, randomised (2:1), double-masked, parallel group, placebocontrolled studies were conducted in the US to assess the clinical safety and efficacy of bromfenac dosed twice daily in the treatment of post-operative inflammation in patients undergoing cataract surgery. In these studies, study substance was administered approximately 24 hours after cataract surgery and continued for up to 14 days. Treatment effect was evaluated up to 29 days.

A significantly greater proportion of patients in the bromfenac group 64.0% vs. 43.3% in the placebo group (p<0.0001) experienced complete clearance of ocular inflammation at study day 15. There was significantly less anterior chamber cells and flare within the first 2 weeks post-surgery (85.1% of patients with flare score of ≤1) vs. placebo (52%). The difference in the rate of inflammation clearance showed as early as day 3.

In a large, well-controlled study that was conducted in Japan, bromfenac was shown to be as effective as pranoprofen ophthalmic solution.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with bromfenac in all subsets of the paediatric population in postoperative ocular inflammation.

Pharmacokinetic Properties

Absorption

Bromfenac efficiently permeates the cornea of cataract patients: A single dose resulted in a mean peak aqueous humour concentrations of 79±68 ng/ml at 150-180 minutes after dosing. Concentrations were maintained for 12 hours in aqueous humour with measurable levels up to 24 hours in major ocular tissues including the retina. Following twice daily dosing with bromfenac eye drops plasma concentrations were not quantifiable.

Distribution

Bromfenac shows high binding to plasma proteins. In vitro, the 99.8% were bound to proteins in human plasma.

No biological relevant melanin binding was observed in vitro.

Studies in rabbits using radio-labelled bromfenac have demonstrated that highest concentrations after topical administration are observed in the cornea followed by the conjunctiva and the aqueous humour. Only low concentrations were observed in the lens and vitreous.

Biotransformation

In vitro studies indicate that bromfenac is mainly metabolised by CYP2C9, which is absent in both iris-ciliary body and retina/choroid and the level of this enzyme in the cornea is less than 1% compared to the corresponding hepatic level.

In orally treated humans unchanged parent compound is the major component in plasma. Several conjugated and unconjugated metabolites have been identified with the cyclic amide being the major urinary metabolite.

Elimination

After ocular administration the half-life of bromfenac in aqueous humour is 1.4 h indicating rapid elimination.

After oral administration of 14C-bromfenac to healthy volunteers, urinary excretion was found to be the major route of radioactive excretions, accounting for approximately 82% while faecal excretion represented approximately 13% of the dose.

Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, ‘repeated-dose’ toxicity, genotoxicity and carcinogenic potential. However, 0.9 mg/kg/day in rats at oral doses (900 times the recommended ophthalmic dose) caused embryofoetal lethality, increased neonatal mortality, and reduced postnatal growth. Pregnant rabbits treated orally with 7.5 mg/kg/day (7500 times the recommended ophthalmic dose) caused increased postimplantation loss.

Animal studies have shown excretion of bromfenac in breast milk when applied orally at doses of 2.35 mg/kg which is 2350 times the recommended ophthalmic dose. However, following ocular administration plasma levels were not detectable.

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