Abstract: Combination Therapy with Methotrexate and Hydroxychloroquine for Rheumatoid Arthritis Increases Exposure to Methotrexate

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Combination Therapy with Methotrexate and Hydroxychloroquine for Rheumatoid Arthritis Increases Exposure to Methotrexate

SAMANTHA J. CARMICHAEL, JOANNE BEAL, RICHARD O. DAY, and SUSAN E. TETT

ABSTRACT.

Objective. To examine the bioavailability of methotrexate (MTX) in the presence of hydroxychloroquine (HCQ), and vice versa, to determine a possible pharmacokinetic explanation for the observation that combination treatment of rheumatoid arthritis with MTX and HCQ has been shown, clinically, to be more potent than MTX used alone.

Methods. In a randomized crossover study, 10 healthy subjects received, on each of 5 dosing occasions, MTX alone as tablets or intravenous solution, HCQ alone as a tablet or oral solution, or a coadministered dose of MTX tablets with an HCQ tablet. The area under the concentration-time curve (AUC) was determined for each subject, on each dosing occasion, for each compound.

Results. The mean AUC for MTX was increased (p = 0.005) and the maximum MTX concentration (C_max) decreased (p = 0.025) when MTX was coadministered with HCQ, compared to MTX administered alone. The time to reach C_max for MTX administration, t_max, was also increased during the coadministration with HCQ (p = 0.072). The AUC of HCQ showed no significant difference (p = 0.957) between any of the dosing occasions.

Conclusion. These results may explain the increased potency of the MTX-HCQ combination over MTX as a single agent and also the sustained effects of MTX when administered with HCQ. In addition, the reduced C_max of MTX observed during the coadministration may explain diminution of acute liver adverse effects. Extra vigilance for MTX adverse effects during combination therapy with HCQ is recommended, especially if renal function is known to be decreased. (J Rheumatol 2002;29:2077-83)

Key Indexing Terms:

METHOTREXATE
HYDROXYCHLOROQUINE
BIOAVAILABILITY
RHEUMATOID ARTHRITIS

From the School of Pharmacy, University of Queensland, Brisbane, Queensland; Department of Clinical Pharmacology, St. Vincent's Hospital, Darlinghurst; and the School of Physiology and Pharmacology, University of New South Wales, Sydney, NSW, Australia.

Funded by NHMRC Project Grant 971087.

S.J. Carmichael, PhD, NHMRC Research Officer; J. Beal, BSc, Research Assistant; S.E. Tett, PhD, Head, School of Pharmacy, University of Queensland; R.O. Day, MD, Director, Department of Clinical Pharmacology, St. Vincent's Hospital, School of Physiology and Pharmacology, University of New South Wales.

Address reprint requests to Dr. S.E. Tett, School of Pharmacy, Steele Building, University of Queensland, Brisbane, Queensland 4072, Australia.

Submitted November 13, 2001; revision accepted April 15, 2002.