title: Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20.
abstract: 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 10(3)), 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.
authors.affiliation: Génétique, Immunothérapie, Chimie et Cancer, Université François Rabelais, Tours, France.
authors.forename: David
authors.initials: D
authors.lastname: Daydé
authors.forename: David
authors.initials: D
authors.lastname: Ternant
authors.forename: Marc
authors.initials: M
authors.lastname: Ohresser
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lerondel
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pesnel
authors.forename: Hervé
authors.initials: H
authors.lastname: Watier
authors.forename: Alain
authors.initials: A
authors.lastname: Le Pape
authors.forename: Pierre
authors.initials: P
authors.lastname: Bardos
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008163:Luminescent Measurements; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab; D014185:Transplantation, Isogeneic; D047368:Tumor Burden / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000069283:Rituximab; D008156:Luciferases