J Clin Pharmacol
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PHARMACOKINETICS AND PHARMACODYNAMICS

Valdecoxib, a COX-2-Specific Inhibitor, Does Not Affect Cardiac Repolarization

Nenad Sarapa, MD, Margaret R. Britto, PhD, Barbara Cotton, MS, Steven R. Cox, PhD, Steven F. Francom, PhD, Na Jin, MS, Emery D. Polasek, MD, Stephen M. Sainati, MD, PhD, Sharon L. Crosby-Sessoms, BA and Joseph C. Fleishaker, PhD

From Clinical Pharmacology (Dr. Sarapa, Dr. Sainati, Ms. Crosby-Sessoms) and Global Statistics and Programming (Ms. Cotton, Ms. Jin), Pharmacia Corp., Skokie, Illinois; Quintiles, Inc., Clinical Pharmacology, Kansas City, Missouri (Dr. Britto); and Clinical Pharmacology (Dr. Cox, Dr. Fleishaker), Global Statistics and Programming (Dr. Francom), and the Clinical Research Unit (Dr. Polasek), Pharmacia Corp., Kalamazoo, Michigan. Dr. Sainati is currently at Takeda Pharmaceuticals North America, Lincolnshire, Illinois.

This double-blind, four-way crossover study assessed the effect of valdecoxib on the QTc interval duration in 25 male and 9 female healthy adults. Subjects received placebo or 40 mg, 80 mg, or 120 mg valdecoxib once daily for 5 days. Serial ECGs were obtained for 24 hours before the first treatment (baseline) and on the 5th day of each treatment. The study was statistically powered to detect a difference of >= 5.6 ms in the average daily QTc change from baseline and a >= 7.8-ms difference in the average maximal daily change from baseline. No QTc prolongation versus placebo (Fridericia's or Bazett's correction) was observed for any valdecoxib dose. A 22% greater than proportional increase in valdecoxib AUC0-24 was observed over the 40- to 120-mg dose range, supporting the conclusiveness of the negative QTc risk assessment even at supratherapeutic doses (up to three times the maximum recommended dose of 40 mg per day) and concentrations. In conclusion, repeated administration of doses up to 120 mg valdecoxib had no effect on cardiac repolarization in healthy volunteers, suggesting that chronic administration of valdecoxib to patients would not increase the risk from cardiac arrhythmia associated with QT prolongation.

Key Words: Valdecoxib • COX-2-specific inhibitor • QT prolongation • pharmacokinetics

Address for reprints: Nenad Sarapa, MD, Department of Clinical Pharmacology, Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL 60077.


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