Pharmacology and Gastrointestinal Safety of Lumiracoxib, a Novel Cyclooxygenase-2 Selective Inhibitor: An Integrated Study

Background & Aims: Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a single study to evaluate potency, selectivity, and effect on the human gastrointestinal tract. Methods: Twenty four healthy subjects (aged 18-45 years, 12 female) received high dose lumiracoxib (800 mg every day), standard dose naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized crossover study. At the start and end of each dosing period, COX-2 selectivity was assessed by ex vivo serum thromboxane B-2 (COX-1) and lipopolysaccharide stimulated prostaglandin (PG) E-2 (COX-2), mucosal injury by endoscopy, and small and large bowel permeability by 0- to 5-hour and 5- to 24-hour Cr-51-EDTA absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and vortex-stimulated ex vivo gastric mucosal PGE(2) synthesis at the end of each treatment period by enzyme immunoassay. Results: Lumiracoxib was well absorbed and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66% inhibition, respectively, vs. placebo), but it differed in being more selective (24% and 97% inhibition of thromboxane B2 vs. placebo). Gastric PGE2 was reduced by 69% by naproxen (P < 0.001 vs. placebo) and 29% by lumiracoxib (P < 0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). Cr-51-EDTA absorption increased significantly with naproxen but not lumiracoxib. Conclusions: Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no endoscopically detected stomach or duodenal injury or changes in bowel permeability.