Clinical Pharmacokinetics and Use of Infliximab
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REVIEW ARTICLE
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Clinical Pharmacokinetics and Use of Infliximab Ulrich Klotz,1 Alexander Teml1 and Matthias Schwab1,2 1
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of ¨ ¨ Tubingen, Tubingen, Germany ¨ ¨ 2 Department of Clinical Pharmacology, University Hospital Tubingen, Tubingen, Germany
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645 1. Clinical Use of Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647 2. Pharmacokinetic Properties of Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650 2.1 Pharmacokinetics in Patients with Crohn’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651 2.2 Pharmacokinetics in Patients with Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 2.3 Pharmacokinetics in Other Populations/Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654 3. Pharmacokinetics and Clinical Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655 4. The Clinical Future of Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
Abstract
Tumor necrosis factor-α (TNFα) is a key proinflammatory cytokine involved in chronic inflammatory diseases. Infliximab, a chimeric (human-murine) monoclonal IgG1 anti-TNFα antibody, is used in the treatment of Crohn’s disease (including fistulising disease) and rheumatoid arthritis (in combination with methotrexate) if standard treatments have failed. The indications for infliximab have recently been expanded to include ankylosing spondylitis, psoriatic arthritis, psoriasis and ulcerative colitis. The biological agent infliximab is given by multiple intravenous infusions in a dosage of 3–5 mg/kg (initially at weeks 0, 2 and 6; subsequently in intervals of 4–8 weeks). In controlled trials, clinical response rates of 20–40% have been achieved with such regimens in Crohn’s disease and rheumatoid arthritis. However, the therapeutic benefits must be balanced against the risks of a variety of severe adverse events (e.g. severe infections including tuberculosis, hepatotoxicity, infusion reactions, serum sickness-like disease and lymphoma). Following single and multiple infusions of infliximab, no relevant differences in median concentration-time profiles have been observed between patients with Crohn’s disease, patients with rheumatoid arthritis and patients with psoriasis. The apparent volume of distribution of the high-molecular-weight infliximab (149.1 kDa) is low (3–6L) and represents the intravascular space. The long
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