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Clinical Pharmacokinetics and Use of Infliximab

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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 persistence in this compartment (elimination half-life 7–12 days, mean residence time 12–17 days) is due to the very low systemic clearance of about 11–15 mL/ hour (0.18–0.25 mL/minute). Elimination of infliximab is most probably accomplished through degradation by unspecific proteases. During multiple infusions (every 4–8 weeks), no accumulation was observed, and serum concentrations and the area under the plasma concentration-time curve of infliximab increased in proportion to the infused dose, indicating linear pharmacokinetics. Co-medication with methotrexate delayed the decline in the serum concentrations of infliximab. When relating serum concentrations to the clinical response in patients with rheumatoid arthritis and patients with Crohn’s disease, it can be assumed that trough concentrations above 1 μg/mL could be used as a kind of therapeutic target. In the future, identification of biomarkers for (non-)response and risk factors for adverse drug reactions would be very helpful. Furthermore, combined biological, pharmacokinetic, pharmacogenomic and clinical studies have not yet been performed and are needed to optimise the therapeutic potential of infliximab, which is currently established as a rescue treatment in refractory patients.

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Acknowledgements

The secretarial help of Mrs U. Hengemühle is appreciated. This work was supported by the Robert Bosch Foundation, Stuttgart, Germany. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany

    Ulrich Klotz, Alexander Teml & Matthias Schwab

  2. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany

    Matthias Schwab

Authors
  1. Ulrich Klotz
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  2. Alexander Teml
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  3. Matthias Schwab
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Correspondence to Ulrich Klotz.

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Klotz, U., Teml, A. & Schwab, M. Clinical Pharmacokinetics and Use of Infliximab. Clin Pharmacokinet 46, 645–660 (2007). https://doi.org/10.2165/00003088-200746080-00002

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  • DOI: https://doi.org/10.2165/00003088-200746080-00002

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