What is Clinically Relevant COX Selectivity? - Part 6: Cyclooxygenase-2-Selective Inhibitors: Translating Pharmacology into Clinical Utility

Clinical endpoints, ascertained through trials, are necessary to determine whether COX-2-specific inhibition translates to efficacy and greater GI safety. Various clinical endpoints have been employed for this purpose. GI symptoms, such as dyspepsia, are poorly correlated to gastric lesion formation, and the role of COX-1 in these events is unclear.(33) Endoscopic data are more favorable, and a baseline and post-treatment comparison should provide strong evidence for ulcerogenesis in a clinical setting.(31) Endoscopic studies remain a surrogate for outcomes studies, which should be sought after as the definitive arbiters of GI safety as well as analgesic/ inflammatory efficacy.

COX-2-selective inhibitors

In light of the collective evidence for COX selectivity, only a few drugs have a COX-1/COX-2 ratio suggesting that limited inhibition of COX-1 would occur at therapeutic levels. Three drugs that have existed for some time-meloxicam, nimesulide, and diclofenac-all have a COX-1/COX-2 ratio in the range of 10 to 30.(33,34) These drugs, while preferentially inhibiting COX-2, have considerable COX-1 inhibitory activity. Meloxicam, nimesulide, and diclofenac show significant inhibition of COX-1 at therapeutic levels.(35-37) Furthermore, large clinical trials have not been able to show a substantial GI benefit with these agents.(30)

Two drugs approved by the US Food and Drug Administration, rofecoxib and celecoxib, have been shown to have the greatest selectivity for COX-2. In vitro and ex vivo studies show that these coxibs have COX-1/COX-2 ratios that are 10- to 100-fold greater than existing nonselective NSAIDs.(21,33,38) Furthermore, ex vivo assays following single doses in normal hosts showed negligible (~10%) inhibition of TXB2 release by platelet COX-1. Unlike rofecoxib, however, celecoxib inhibited release of TXB2 in a dose-dependent manner and had an interindividual variation in response that ranged from 10% to more than 80% inhibition.(39) Both rofecoxib and celecoxib have been examined in clinical trials large enough to have sufficient statistical power for detection of clinical specificity.(5,6) The results fulfilled expectations that COX-2-specific inhibitors could achieve efficacy equal to nonselective NSAIDs with less GI toxicity (see article by Scheiman, this supplement). Additional COX- 1-sparing drugs (etoricoxib, valdecoxib, and COX- 189; see article on the development of coxibs in this supplement) are in preclinical and clinical development. The outcomes of clinical trials evaluating coxibs are discussed in detail in a recent review.(40)

Cronstein BN. Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. Cleve Clin J Med 2002;69:SI13-19.

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