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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3765-3772. Prepublished online as a Blood First Edition Paper on November 24, 2008; DOI 10.1182/blood-2008-08-175125. This Article Full Text (PDF) All Versions of this Article: blood-2008-08-175125v1 113/16/3765    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dayde, D. Articles by Cartron, G. Search for Related Content PubMed PubMed Citation Articles by Dayde, D. Articles by Cartron, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 19, 2008 Accepted November 15, 2008 Tumor burden influences exposure and response to rituximab: pharmacokinetic - pharmacodynamic modelling using a syngeneic bioluminescent murine model expressing human CD20 David Dayde, David Ternant, Marc Ohresser, Stephanie Lerondel, Sabrina Pesnel, Herve Watier, Alain Le Pape, Pierre Bardos, Gilles Paintaud, and Guillaume Cartron* Universite Francois Rabelais de Tours, GICC, Tours, France CNRS, UMR 6239, Tours, France CNRS, UPS44, TAAM UPS44 - CIPA-CNRS, Orleans, France Department of Immunology, CHRU de Tours, Tours, France INSERM U618, Proteases et vectorisation pulmonaire, Tours, France Department of Pharmacology-Toxicology, CHRU de Tours, Tours, France CHU Lapeyronie, Service d'Hematologie et Biotherapies, Montpellier, France * Corresponding author; email: guillaume.cartron{at}med.univ-tours.fr. Clinical studies have shown a large interindividual variability in rituximab exposure and its significant influence on clinical response in patients receiving similar doses of antibody. The aim of this study was to evaluate the influence of tumor burden on dose-concentration-response relationships of rituximab. Murine lymphoma cells (EL4, 8 x 103) transduced with human CD20 cDNA and transfected with luciferase plasmid (EL4-huCD20-Luc) were intravenously injected to C57BL/6J mice. Tumor burden detection, dissemination and progression were evaluated quantitatively by in vivo bioluminescence imaging. Different doses of rituximab (6 mg/kg, 12 mg/kg, 20 mg/kg or 40 mg/kg) were infused thirteen days after lymphoma cell inoculation and rituximab serum concentrations were measured by ELISA. Without rituximab, all mice developed disseminated lymphoma and died within 30 days whereas a significant dose-response relationship was observed in mice receiving rituximab. The 20 mg/kg dose was adequate to study interindividual variability in response since 23% of mice were cured, 59% had partial response and 18% had disease progression. Rituximab concentrations were inversely correlated with tumor burden, mice with low tumor burden having high rituximab concentrations. Furthermore rituximab exposure influenced response and survival. Finally, using a pharmacokinetic-pharmacodynamic model, we demonstrated that tumor burden significantly influenced rituximab efficacy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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