Clinical pharmacology of selective COX-2 inhibitors

The discovery of cyclooxygenase (COX)-2 has provided the rationale for the development of a new class of nonsteroidal antiinflammatory drugs (NSAIDs), the selective COX-2 inhibitors (denominated coxibs), with the aim of reducing the gastrointestinal (GI) toxicity associated with the administration of NSAIDs by virtue of COX-1 sparing. Rofecoxib and celecoxib are the first selective COX-2 inhibitors approved by the FDA and EMEA for the treatment of rheumatoid arthritis (RA), osteoarthritis (OA) and for relief of acute pain. Rofecoxib has been shown to spare COX-1 activity ex vivo, in platelets and gastric mucosa, when administered at therapeutic doses or above. In a large clinical trial, rofecoxib has been demonstrated to halve the incidence of serious upper GI events vs a nonselective NSAID. Recently, other selective COX-2 inhibitors with different COX-1/COX-2 selectivity and pharmacokinetic features have been developed, i.e. valdecoxib, parecoxib, etoricoxib and lumiracoxib. The improved biochemical selectivity of valdecoxib vs celecoxib in vitro (COX-1/COX-2 ratio: 60 vs 30, respectively) may be clinically relevant leading to an improved GI safety. Interestingly, parecoxib, a pro-drug of valdecoxib, is the only injectable coxib. Etoricoxib, showing only a slightly higher COX-2 selectivity than rofecoxib in vitro (COX-1/COX-2 ratio: 344 vs 272, respectively), has been reported to cause a similar specific COX-2 inhibition ex vivo that should translate into comparable GI safety. Lumiracoxib, the most selective COX-2 inhibitor in vitro (COX-1/COX-2 ratio: 400), is the only acidic coxib. It has been hypothesized that this pecular chemical feature may lead to an enhanced concentration in inflammatory sites that may translate into an improved clinical efficacy. The results of clinical trials have shown that coxibs have a comparable clinical efficacy and renal toxicity and an improved GI safety vs nonselective NSAIDs. Whether the different pharmacodynamic and pharmacokinetics features of the various coxibs will produce detectable differences in efficacy and toxicity remains to be evaluated in appropriate comparative randomized clinical studies.