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Characterization of Etoricoxib, a Novel, Selective COX-2 Inhibitor

From the Clinical Development Laboratory (Ms. Dallob), Clinical Biostatistics (Ms. Wong), Clinical Research (Dr. DeTora), and Clinical Pharmacology (Dr. Gertz, Dr. Wagner, Dr. Gottesdiener), Merck Research Laboratories, Rahway, New Jersey; Division of Gastroenterology, University Hospital, Nottingham, United Kingdom (Dr. Hawkey, Mr. Wight); Division of Clinical Pharmacology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania (Dr. Greenberg, Dr. Waldman); Department of Clinical Pharmacology, University Hospital, Leuven, Belgium (Dr. De Schepper); and Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania (Dr. Agrawal).

Etoricoxib is a potent selective COX-2 inhibitor in man. Ex vivo whole-blood assays assessed COX-2 inhibition after oral administration of etoricoxib in single (5-500 mg) and multiple (25-150 mg) once-daily doses to healthy human subjects. A separate study examined ex vivo gastric mucosal PGE₂ synthesis after etoricoxib (120 mg qd), naproxen (500 mg bid), or placebo for 5 days. The effect of etoricoxib 120 mg qd on the COX-1-mediated antiplatelet effects of low-dose aspirin (ASA) was also assessed. The mean (time)-weighted average inhibition (WAI) of lipopolysaccharide (LPS)-stimulated PGE₂ (COX-2 assay) versus placebo was dose related after single (range: 3.1%-99.1%) and multiple doses (range: 52.5%-96.7%). PGE₂ remained significantly inhibited 24 hours postdose at steady state. Inhibition of LPS-stimulated PGE₂ showed a strong relationship with etoricoxib plasma concentrations; ex vivo, IC₅₀ was almost identical to in vitro. Multiple dosing of etoricoxib (up to 150 mg qd) showed no important effects on serum TXB₂, bleeding time, or platelet aggregation (COX-1-mediated effects). The nonselective nonsteroidal anti-inflammatory (NSAID) naproxen significantly inhibited (78%) ex vivo prostaglandin synthesis in gastric mucosa; etoricoxib had no effect. Etoricoxib did not interfere with the antiplatelet effects of low-dose ASA, as assessed by serum TXB₂ and platelet aggregation. Etoricoxib was generally well tolerated, even at doses above the clinical dose range. Based on these results, etoricoxib is a potent selective inhibitor of COX-2 after single and multiple dosing regimens and does not inhibit prostaglandin synthesis in the gastric mucosa, even at doses above the clinical dose range of 60 to 120 mg.

Key Words: Etoricoxib • COX-2 inhibitor • NSAIDs • whole-blood assays • gastric biopsy study • pharmacokinetics • pharmacodynamics • aspirin

Address for reprints: Aimee Dallob, RY50-100, Box 2000, Rahway, NJ 07065.

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