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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 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 Citation Map 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 Daydé, D. Articles by Cartron, G. Search for Related Content PubMed PubMed Citation Articles by Daydé, D. Articles by Cartron, G. Related Collections Immunobiology Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20 David Daydé1,2, David Ternant1,2, Marc Ohresser1,2, Stéphanie Lerondel3, Sabrina Pesnel3, Hervé Watier1,2,4, Alain Le Pape3,5, Pierre Bardos1,2,4, Gilles Paintaud1,2,6, and Guillaume Cartron7,8 1 Génétique, Immunothérapie, Chimie et Cancer, Université François Rabelais, Tours; 2 Unité Mixte de Recherche 6239, Centre National de la Recherche Scientifique, Tours; 3 Centre d'Imagerie du Petit Animal, Centre National de la Recherche Scientifique, Orléans; 4 Laboratoire d'immunologie, Centre Hospitalier Régional Universitaire, Tours; 5 Protéases et Vectorisation Pulmonaire U618, Inserm, Tours; 6 Laboratoire de Pharmacologie Toxicologie, Centre Hospitalier Régional Universitaire, Tours; 7 Biothérapies des Cellules Souches Normales et Cancéreuses U847, Inserm, Montpellier; and 8 Service d'Hématologie et Biothérapies, Centre Hospitalier Universitaire, Montpellier, France 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 into C57BL/6J mice. Tumor burden detection, dissemination, and progression were evaluated quantitatively by in vivo bioluminescence imaging. Different doses of rituximab (6, 12, 20, or 40 mg/kg) were infused 13 days after lymphoma cell inoculation, and rituximab serum concentrations were measured by enzyme-linked immunosorbent assay. 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 because 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 had 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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