title: Characterization of etoricoxib, a novel, selective COX-2 inhibitor.
abstract: 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) vcrsus 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 (approximately 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.
authors.affiliation: Clinical Development Laboratory, Merck Research Laboratories, Rahway, New Jersey, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Dallob
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hawkey
authors.forename: Howard
authors.initials: H
authors.lastname: Greenberg
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wight
authors.forename: Paul
authors.initials: P
authors.lastname: De Schepper
authors.forename: Scott
authors.initials: S
authors.lastname: Waldman
authors.forename: Peggy
authors.initials: P
authors.lastname: Wong
authors.forename: Lisa
authors.initials: L
authors.lastname: DeTora
authors.forename: Barry
authors.initials: B
authors.lastname: Gertz
authors.forename: Nancy
authors.initials: N
authors.lastname: Agrawal
authors.forename: John
authors.initials: J
authors.lastname: Wagner
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D019540:Area Under Curve; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D004311:Double-Blind Method; D004361:Drug Tolerance; D000077613:Etoricoxib; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009288:Naproxen / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013450:Sulfones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011725:Pyridines; D013450:Sulfones; D009288:Naproxen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D000077613:Etoricoxib