ByDeepinder K. Dhaliwal, MD

February 15, 2006

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Potency and pharmacokinetics of NSAIDs

ByDeepinder K. Dhaliwal, MD

Nonsteroidal anti-inflammatory drugs are an important class of drugs in the management of postoperative inflammation in patients undergoing cataract surgery. In order to understand how this class of drugs works and how individual drugs within the class differ, the pharmacology and pharmacokinetic properties of NSAIDs must be examined. However, first the focus must be on the pathophysiology of the inflammatory response to gain a full appreciation of the mechanism of action of these agents.

Pathophysiology of inflammation

Any surgical trauma will release cell membrane phospholipids that are converted by phospholipase A2 into arachidonic acid. The arachidonic acid can then travel one of two main pathways: the lipooxygenase pathway, leading to the production of leukotrienes, or the cyclooxygenase (COX) pathway, which converts arachidonic acid into prostaglandins. If arachidonic acid takes the COX pathway, the result will be inflammatory or protective prostaglandins, depending on whether production of these substances is catalyzed by the COX-1 or COX-2 enzyme.

COX-1 is a constitutive enzyme. It is present in most normal cells and tissues and catalyzes production of prostaglandins that mediate normal physiological processes; it can be considered a “housekeeping” enzyme that maintains homeostasis. Therefore, the COX-1 enzyme has many desirable effects including the maintenance of the gastric mucosa, normal platelet aggregation and renal blood flow.

Conversely, COX-2 is an inducible enzyme that is found primarily in immune and inflammatory cells and is synthesized in response to inflammation or carcinogenesis. This enzyme catalyzes the production of prostaglandins that mediate the inflammatory process, resulting in symptoms such as pain, fever, headache and other effects that occur secondary to pro-inflammatory conditions. COX-2 can lead to a range of undesirable effects including vascular permeability, miosis, increased IOP and disruption of the blood-aqueous barrier.

Unlike corticosteroids, which block both the leukotriene and cyclooxygenase pathways, NSAIDs interrupt the activity of the COX-1 and COX-2 enzymes. However, NSAID efficacy depends on factors such as tissue penetration, relative selectivity for COX-1 and COX-2 and potency in inhibiting enzymatic activity.

Penetration into ocular tissues

It is essential to understand the extent to which individual NSAIDs penetrate into target tissues. Penetration is critical in that if the drug cannot reach the site of action, then the potency of the drug is irrelevant. Control of inflammation following cataract surgery can be achieved only when sufficient levels of NSAID molecules penetrate the cornea to effectively suppress prostaglandin formation within the ocular tissues.

NSAID penetration can vary considerably among agents. One pharmacokinetic study assessed the penetration of a single drop of radioactive 0.36% bromfenac (Figure 1). These data were compared with a similar study of radiolabeled 0.3% nepafenac (Figure 2). Drug concentrations in the cornea, iris, ciliary body, aqueous humor, choroid and retina were measured over time. Results demonstrated a higher drug concentration with bromfenac compared with nepafenac; furthermore, bromfenac remained in the retina, aqueous humor and choroid for a longer duration than nepafenac. The concentration of bromfenac was matched with that of nepafenac so results could be compared.

Figure 1: Concentrations of Radioactivity in Ocular Tissues

Study assessing the penetration of a single drop of radioactive 0.36% bromfenac.

(Figure courtesy of Monte S. Dirks, MD)

Figure 2: Penetration of 14C-Nepafenac

Study assessing the penetration of a single drop of radiolabeled 0.3% nepafenac.

(Figure courtesy of Deepinder K. Dhaliwal, MD)

Selectivity and potency of NSAIDs

After reaching its target site, an NSAID should exhibit a high degree of selectivity against the COX-2 enzyme while not affecting the COX-1 enzyme. However, the extent to which this selectivity occurs clinically depends on the potency and selectivity of the agent.

The inhibitory concentration (IC₅₀) of an NSAID is the concentration of drug required to inhibit enzyme activity by 50%; the smaller the value, the more potent the agent. The relative selectivity of a specific NSAID is expressed as a ratio of the IC₅₀ for COX-1 and COX-2 (IC₅₀COX-2/IC₅₀COX-1); the smaller the ratio, the more specific the agent is for COX-2 (Figure 3). IC₅₀ values can vary among models depending on the source of the cyclooxygenase. A variety of models for COX activity exist including human pure enzyme, whole blood and cells such as macrophages, platelets and leukocytes.

The IC₅₀COX-1 for bromfenac is 0.53 uM, and the COX-2 is 0.023 uM; for diclofenac COX-1 is 0.95 uM, COX-2 is 0.085 uM; for amfenac COX-1 is 0.25, COX-2 0.15, and for nepafenac COX-1 is 64.3, COX-2 is >100.

Figure 3: NSAIDs: COX-2 vs COX-1: Selectivity and Potency

COX-2 vs. COX-1 in bromfenac, diclofenac, amfenac, and napafenac.

(Figure courtesy of Monte S. Dirks, MD)

Summary

Topical NSAIDs that achieve good penetration into ocular tissues and exhibit a high degree of selectivity and potency against the COX-2 enzyme are good choices for the control of inflammation following cataract surgery. The penetration, selectivity and potency of bromfenac allow this agent to achieve therapeutic levels in the eye and improve postoperative outcomes with only twice-daily administration.

References

Data on file, ISTA Pharmaceuticals, Inc.

Data from nepafenac patent no. US 6,646,001 B2. Nov. 11, 2003.

Gamache DA, Graff G, Brady MT, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. Assessment of anti-inflammatory efficacy. Inflammation. 2000;24(4):357-370.

Discussion

David F. Chang, MD: The findings discussed in Dr. Dhaliwal’s presentation are important because good prospective head-to-head clinical studies comparing topical ocular NSAIDs do not exist. Dr. Dhaliwal, is the less frequent dosing requirement with bromfenac compared with other NSAIDs due to the potency of the drug?

Deepinder K. Dhaliwal, MD: Yes.

Chang: How were the IC₅₀levels determined? Were these data from in vitro studies?

Dhaliwal: Yes. These data were from sheep testes and macrophage models. They were compiled data, not head-to-head comparisons. Although the studies were not done by the same investigator and the drug concentrations were slightly different, definite differences in enzyme inhibition between the various NSAIDs were identified.

Chang: What are your clinical impressions in terms of potency of the various NSAIDs?

Roy S. Chuck, MD: Bromfenac is definitely true to the indication at twice-a-day dosing in that it is effective at this dosing schedule.

Monte S. Dirks, MD: Another factor to consider is pain control. I am impressed with the pain relief we get with twice-daily administration of bromfenac after only a couple of doses. Bromfenac is a potent and effective medication in patients with corneal abrasions.

Chang: How do you use NSAIDs following refractive surgery?

Dirks: Our refractive surgery department uses bromfenac postoperatively, especially for photorefractive keratectomy (PRK). Actually, the U.S. Army also perform a number of PRK procedures, as opposed to LASIK, and use bromfenac in their program (in a conversation with Steven Grimes, MD, July 2005).

William B. Trattler, MD: I started using bromfenac about 4 months ago, and it has worked well with my surface laser patients. I primarily perform surface laser procedures, and bromfenac has been helping pain control in my patients.

Dhaliwal: Are you dosing it preoperatively or postoperatively?

Trattler: I do not initiate it preoperatively. I prescribe bromfenac along with prednisolone acetate and an antibiotic four times a day. This treatment regimen is highly effective in my patients.

Dhaliwal: How long do you administer bromfenac?

Trattler: I use bromfenac as long as the contact lens is in place following surgery. Once the epithelium heals completely, I discontinue the nonsteroidal agent.

Barry A. Schechter, MD: Bromfenac also provides effective pain control following trabeculectomy.

Chang: What is the importance of NSAID penetration back to the retina or choroid? Nepafenac is touted as having good penetration into these tissues, which is not something that has been previously considered with commercially available NSAIDs.

Schechter: Obviously, preventing cystoid macular edema (CME) is of primary importance. Drug penetration to the back of the eye is essential.

Chang: The pathogenesis of CME is thought to involve the breakdown of the blood-aqueous barrier, and it has been assumed that topical NSAIDs treat this process in the anterior segment. Because CME probably results from prostaglandin-mediated breakdown of the blood-retinal barrier, NSAID penetration into the retina might make a difference; however, I think this is still unclear. In any case, based on the data just presented, it appears that bromfenac may achieve better penetration than nepafenac into the retina and choroid, reaching higher levels for longer periods of time. However, a head-to-head comparison would need to confirm.

Dhaliwal: It is important to point out that the formulation of bromfenac used in this study was greater than the commercial formulation. The study used 0.3% of bromfenac and 0.1% of the commercial formulation.

Chang: Are there any comparable data on diclofenac or ketorolac?

Dhaliwal: Not to my knowledge.

Chang: Posterior segment NSAID tissue penetration is an interesting issue and one that we look forward to learning more about. The animal studies have been useful and have provided a good overview of the pharmacokinetics of bromfenac.