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

  • Dallob, Aimee MS
  • Hawkey, Christopher J. MD
  • Greenberg, Howard MD
  • Wight, Nicholas MRCP
  • De Schepper, Paul MD, PhD
  • Waldman, Scott MD, PhD
  • Wong, Peggy MS
  • DeTora, Lisa PhD
  • Gertz, Barry MD, PhD
  • Agrawal, Nancy PhD
  • Wagner, John MD, PhD
  • Gottesdiener, Keith MD

  • 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). All research reported in this article was funded by grants from Merck & Co. Dr. Hawkey is a paid consultant to Merck & Co.

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

The authors would like to acknowledge the following people for their contributions: Mary Flynn and Lynn Wildonger performed the assays whose results are described above. Dr. Wesley Tanaka, head of the Clinical Development Laboratory, provided essential guidance and support. Jo Brough helped conduct the gastric biopsy study at Dr. Hawkey's site at the University of Nottingham. Scott A. Waldman is the Samuel M. V. Hamilton Professor of medicine at Jefferson Medical College, Thomas Jefferson University. Sandi Van Buren and Joanne Burke coordinated the platelet aggregation studies at Thomas Jefferson University. Dr. De Schepper would like to acknowledge the important contributions of Drs. Van Hecken and Depre to the conduct of the single-dose study. Dr. Van Iersel conducted and Dr. Gerrits contributed to the multiple-dose study. The Merck-based authors gratefully acknowledge Drs. De Lepeleire and Calder for monitoring those studies conducted in Belgium (single-dose) and the United Kingdom (gastric biopsy), as well as Josee Cote and David Ebel for study monitoring in the United States. Catherine Matthews and Eric Woolf developed the analytical methods and conducted the assays used to determine etoricoxib plasma concentrations. Brett Musser and Uma Kher provided the primary statistical analyses of two individual studies. Christine Nyers and Jamie Switzer provided manuscript support.

Submitted for publication June 30, 2002; revised version accepted March 12, 2003.

The Journal of Clinical Pharmacology 43(6):p 573-585, June 2003.

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 PGE2showed 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.

Copyright ©2003 SAGE Publications