Brooks and Kubler Cush et al 2006). NSAIDs inhibit the COX-mediated synthesis of prostaglandins, which are important inter- mediaries in the development of inflammation and pain. Traditional NSAIDs inhibit both constitutive COX-1 and inducible COX-2, two processes which are believed to be responsible for the adverse effects (primarily gastrointestinal toxicity) and clinical benefits of treatment, respectively (Warner and Mitchell 2004). Dyspeptic upper gastro- intestinal symptoms with chronic use of traditional NSAIDs often lead to discontinuation by the patient with consequent inadequate pain control, switching from one NSAID to another, or the addition of a gastroprotective agent to prevent or treat upper gastrointestinal symptoms or clinical events (Watson et al 2004). Major gastrointestinal complications, such as perforation, ulcers, and bleeding may require visits to the emergency department, hospitalization, and endoscopic or barium tests. In addition to discomfort and inconvenience for the patient, the costs of dealing with these adverse events are substantial (Moore et al 2004). In contrast, selective COX-2 inhibitors have greater affinity for COX-2 than COX-1. Clinical evidence has shown that selective COX-2 inhibitors have comparable efficacy with traditional NSAIDs in the treatment of arthritis and pain, but offer the major advantage of reduced gastro- intestinal toxicity (Warner and Mitchell 2004), thus providing physicians with an important therapeutic alternative. Recently, reports from two long-term studies in patients with a history of colorectal adenomas have detailed an increased risk of cardiovascular events associated with the COX-2 inhibitors celecoxib and rofecoxib compared with placebo (Bresalier et al 2005; Solomon et al 2005), leading to questions about the cardiovascular safety of these agents (Drazen 2005; Psaty and Furberg 2005), and highlighting the importance of careful patient selection based on the benefits and risks of treatment. This article will review available data regarding the efficacy and tolerability of etoricoxib, a selective COX-2 inhibitor that has been evaluated in arthritis and pain. Pharmacology In vitro, etoricoxib exhibits a greater selectivity for COX-2 over COX-1 compared with the COX-2 inhibitors rofecoxib, valdecoxib, and celecoxib (Riendeau et al 2001; Tacconelli et al 2002). Etoricoxib binds competitively to COX-2 with 1:1 stoichiometry in a reversible, noncovalent manner (Riendeau et al 2001). In human whole blood assays, etoricoxib inhibited COX-2 with an IC50 of 1.1 ± 0.1 µM, compared with an IC50 of 116 ± 8 µM for COX-1, representing 46 106-fold selectivity for COX-2 over COX-1 (Riendeau et al 2001). No inhibitory effect was observed against a wide range of other receptors and enzymes evaluated. Selective COX-2 inhibition was also observed in ex vivo blood samples from healthy human volunteers who received etoricoxib at various therapeutic and supratherapeutic doses (Dallob et al 2003). Etoricoxib produced markedly less interference with the cardioprotective COX-1-mediated antiplatelet activity of low- dose aspirin in vitro than other NSAIDs including (in ascending order of aspirin antagonism) rofecoxib, valdecoxib, celecoxib, and ibuprofen, reflecting the lower affinity of etoricoxib for COX-1 (Ouellet et al 2001). These findings are consistent with results from clinical studies in which ibuprofen, but not rofecoxib (Catella-Lawson et al 2001) or etoricoxib (Wagner et al 2001), antagonized aspirin antiplatelet activity. Etoricoxib showed potent, dose- dependent efficacy similar to other NSAIDs in animal models of acute inflammation, hyperalgesia, pyresis, and chronic adjuvant-induced arthritis (Riendeau et al 2001). Preclinical and clinical data were consistent with the gastrointestinal tolerability of selective COX-2 inhibition; no effects on gastrointestinal integrity were observed in animal models as measured by urinary or fecal excretion of 51creatinine- ethylenediamine tetraacetic acid (51Cr-EDTA), an inert compound that is not taken up by extravascular tissue after its absorption from the gastrointestinal tract, but is completely excreted by the kidney (Riendeau et al 2001). Inhibition of prostaglandin synthesis in the gastric mucosa was not significantly different from that of placebo in human volunteers (Dallob et al 2003). In healthy volunteers, oral etoricoxib is rapidly and completely absorbed. It reaches Cmax after approximately 1 hour and has up to 100% absolute bioavailability (Agrawal, Porras, et al 2003; Rodrigues et al 2003). Absorption is slowed, but not diminished, following a high-fat meal meaning that etoricoxib can be administered without dietary consideration (Agrawal, Porras, et al 2003). Etoricoxib shows linear pharmacokinetics through doses at least 2-fold higher than the maximum anticipated clinical dose (120 mg) (Agrawal, Porras, et al 2003). Steady state conditions are reached after 7 days of daily administration, with an accumulation half-life of approximately 22 hours and an apparent terminal half-life of approximately 25 hours (Agrawal, Porras, et al 2003), supporting once-daily dosing. Etoricoxib is extensively metabolized and excreted mostly in the urine, with less than 1% of the oral dose recovered intact from urine (Rodrigues et al 2003). It is metabolized primarily by 6´-methyl hydroxylation in human Therapeutics and Clinical Risk Management 2006:2(1)