Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (CO X-2). Methotrexate is a disease-modifying agent with a narrow therapeutic i ndex frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheum atoid arthritis. This was a randomized, double-blind, placebo-controlled st udy in 25 rheumatoid arthritis patients on stable doses of methotrexate. Pa tients received oral methotrexate (7.5 to 20 mg) on days-1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexa te and its major although inactive metabolite, 7-hydroxymethotrexate. The A UC(0-) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/ day-1, and day 211day-1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93 , 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 fo r all comparisons to day -1). All AUC(0-) GMR and C-max GMR 90% Cls fell wi thin the predefined comparability limits of (0.80, 1.25). Similar results w ere observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofe coxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasm a concentrations or renal clearance (tested at the highest dose of rofecoxi b) of methotrexate in rheumatoid arthritis patients. (C) 2001 the American College of Clinical Pharmacology.