Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans

Objective: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxy genase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-infl ammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen princ ipally derive from COX-2 inhibition. The purpose of this study was to evalu ate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx(TM)), characterized in vitro as a COX-2 inhibitor. Methods: Four panels of healthy men (n = 8 per panel) were administered rof ecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time poin ts post-dose. Results: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing wi th an accumulation ratio close to 2 for all doses. COX-2 inhibitory activit y as assessed by average inhibition of whole blood lipopolysaccharide-stimu lated prostaglandin E-2 over the 8-h post-dose period on day 14 was 0.3, 67 , 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatme nt groups, respectively. No treatment group showed significant inhibition o f COX-1 as assessed by thromboxane B-2 generation in clotting whole blood. Side effects were mild and transient. Conclusion: The results indicate that rofecoxib is a potent and specific in hibitor of COX-2 in humans even at doses more than tenfold higher than thos e associated with efficacy in patients with osteoarthritis.