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RHEUMATOLOGY

Lumiracoxib Does Not Affect Methotrexate Pharmacokinetics in Rheumatoid Arthritis Patients

Senior Clinical Pharmacology Scientist, Exploratory Clinical Development, Novartis Pharma AG, Basel, Switzerland

Christiane M Rordorf, MD

Clinical Pharmacology Expert, Exploratory Clinical Development, Novartis Pharma AG, Basel

Slavica Milosavljev, PhD

Labhead, BAPK, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Janice M Branson, MSc BSc

Exploratory Clinical Development Biostatistician, Biostatistics and Statistical Reporting, Novartis Pharma AG, Basel

Gérard H Chales, MD

Professor and Head of Rheumatology Department, Hôpital Sud Rennes, Rennes, France

Robert R Juvin, MD PhD

Professor of Medicine, Rheumatology Department, Hôpital Michallon Grenoble, Grenoble, France

Pierre Lafforgue, PhD

Professor and Chief of Rheumatology Department, Hôpital de la Conception, Marseille, France

Jean Marie Le Parc, MD

Professor and Head of Rheumatology Department, Hôpital Ambroise Paré Boulogne, Billancourt, France

Christian G Tavernier, MD

CHRU Dijon, Dijon, France

Olivier C Meyer, MD

Professor and Head of Rheumatology Unit, Hôpital Bichat-Claude Bernard, Paris, France

Reprints: Stefan N Hartmann PhD, Novartis Pharma AG, WSJ-27.3.106, 4002 Basel, Switzerland, fax 41 61 324 29 59, stefan.hartmann{at}pharma.novartis.com

BACKGROUND: Methotrexate and nonsteroidal antiinflammatory drugs are frequently coadministered in the treatment of rheumatoid arthritis (RA).

OBJECTIVE: To evaluate the effect of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, on methotrexate pharmacokinetics and short-term safety in patients with RA.

METHODS: This multicenter, randomized, double-blind, placebo-controlled crossover study enrolled 18 patients (mean age 49.1 y) with stable RA. Patients were randomized to receive methotrexate 7.5–15 mg orally once weekly plus either lumiracoxib 400 mg/day or placebo for 7 days. Patients then received the other treatment combination for an additional 7 days. Serial blood and urine were collected for 24 hours after the methotrexate dose on day 1 (methotrexate alone) and days 8 and 15 (combination treatment).

RESULTS: Plasma methotrexate pharmacokinetics (AUC_0–t, maximum concentration [C_max], time to C_max) and methotrexate protein binding were similar for methotrexate alone (108.0 ng·h/mL, 26.7 ng/mL, 1.5 h, and 57.1%, respectively), methotrexate/lumiracoxib (110.2 ng·h/mL, 27.5 ng/mL, 1.0 h, and 53.7%, respectively), and methotrexate/placebo (101.8 ng·h/mL, 22.6 ng/mL, 1.0 h, and 57.0%, respectively). Similarly, no clinically significant difference was found in the urinary excretion of methotrexate. Mean exposure to the 7-OH metabolite was lower when methotrexate was given with lumiracoxib compared with placebo, shown by a reduction in AUC and C_max, although similar amounts of the metabolite were recovered in urine following both lumiracoxib and placebo. Coadministration of methotrexate and lumiracoxib was well tolerated.

CONCLUSIONS: Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.

Key Words: lumiracoxib, methotrexate, 7-OH-methotrexate, pharmacokinetics, rheumatoid arthritis

Published Online, August 31, 2004. www.theannals.com, DOI 10.1345/aph.1E044

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