Surgery
Figure 3: Two Separate Animal Studies, Conducted under a Common Protocol Demonstrating Ocular-tissue Concentrations of 14C-bromfenac (A) or 14C-nepafenac (B) following a Single Topical Dose (Three Times the Commercial Strength) to Rabbits
A 10 14C-Bromfenac
at the fourth position of the phenyl ring increases the duration of analgesic and anti-inflammatory activity.1
Penetration of Ocular Tissues
The unique bromination of amfenac can increase lipophilicity, resulting in enhanced penetration of bromfenac through the cornea and other ocular tissues. Baklayan et al. presented data from two separate but similar studies in which bromfenac and nepafenac were administered at three times the commercial dose in an animal model.24
1
0.1
0.01
Bromfenac achieved measurable levels in all major ocular tissues that were detectable at 24 hours, but no significant levels of nepafenac/amfenac were detected in the aqueous humour and choroid after 12 hours and in the retina after six hours (see Figure 3). In the same report, Baklayan et al. presented data from a similar study in which bromfenac was instilled at normal commercial strength, with similar results; peak concentrations of bromfenac were observed at or before two hours, with measurable levels in all major ophthalmic tissues over 24 hours.
0.001 0 612 Time (hours) B 10 14C-Nepafenac 18 24 Sustained Therapeutic Activity
In humans, absorption of bromfenac occurs within 15 minutes, with peak aqueous humour concentration at 150–180 minutes (see Figure 4).24,29
These early peak concentrations in aqueous humour remain above the concentration required to inhibit COX-2 by 50%
1
(IC50) for more than 12 hours, suggesting that BID dosing is sufficient to maintain anti-inflammatory activity. Cyclo-oxygenase Inhibition
0.1
NSAIDs vary in their relative potency against COX-1 and COX-2. In the post-cataract surgery setting, COX-2-specific activity is important because it is this form of the enzyme that is believed to be the primary mediator of ocular inflammation.1
Although the exact plasma 0.01
concentration of bromfenac following ocular administration is unknown, the relative potency is assessed by determining the concentration of drug required to inhibit COX enzyme activity by 50% (IC50). A smaller IC50 value signifies greater inhibition of the enzyme.29
0.001 0 612 Time (hours) Cornea Retina Iris-ciliary body Choroid Aqueous humour
A: Detectable levels in all ocular tissues through the 24-hour time-point; B: Retina not detectable at six hours and aqueous humour and choroid not detectable at 12 hours. Reproduced from Baklayan et al., 2008.24
However, there is evidence that a substantial proportion of nepafenac is not converted to amfenac within the eye, leading to reduced PG inhibition.26
Nepafenac is an inactive precursor of amfenac, which can penetrate the corneal epithelium. Nepafenac must then be converted to the active amfenac within the eye before it can have any anti-inflammatory effect.25
18 24
A number of in vitro studies have been conducted. Such studies have shown that the inhibitory effects of bromfenac on COX-2 are 3.7 times greater than those of diclofenac,30 of amfenac31
and 18 times greater than those of ketorolac.32
study, Kida et al. compared the ophthalmic NSAIDs, diclofenac, ketorolac, nepafenac and bromfenac, and found that bromfenac was approximately three to four times more potent than the other three formulations in inhibiting the COX-2 enzyme (see Table 2).33
6.5 times greater than those In another
It should
be noted that the study designs and technologies used in in vitro studies differ, making interpretation of the clinical impact difficult. However, these studies have invariably shown that the inhibition of PG synthesis with bromfenac – and hence in vitro potency, as
measured by its high COX-1/COX-2 IC50 ratio – was preferentially through COX-2 inhibition, resulting in greater inhibitory effect than most other available NSAIDs;1,10,15,29
therefore, bromfenac is a unique
Bromfenac is structurally identical to amfenac, with the key exception of a bromine atom at the fourth carbon atom of the phenyl ring.27
The addition of the bromine atom imparts important characteristics to the bromfenac molecule that distinguish it from other NSAIDs.28
First, bromine enhances the lipophilicity of the molecule and facilitates its penetration through the cell membrane of various tissues, including ocular tissues. Second, bromination
22
and highly potent NSAID. Clinical Efficacy
Two phase III, double-masked, placebo-controlled clinical trials were performed in the US to evaluate the efficacy, safety and tolerability of bromfenac ophthalmic 1mg/ml eye drop solution in treating post-operative inflammation and pain after cataract surgery. The subjects were randomly assigned to either bromfenac twice daily for
EUROPEAN OPHTHALMIC REVIEW
Concentration (μg equivalent/g)
Concentration (μg equivalent/g)
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