title: Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group.
abstract: Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcγRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL.
  
  
  
  Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance.
  
  
  
  Target-mediated elimination rate constant increased with the baseline CD20 count on circulating B cells (p = 0.00046) and in patients with the FCGR3A-158VV genotype (p = 0.0016). Physiologic elimination of antigen was lower in the Binet C disease stage (p = 0.00018). The effects of these covariates on rituximab concentrations were mainly visible at the beginning of treatment. Body surface area also increased central and peripheral volumes of distribution (p = 1.3 × 10-5and 0.0015, respectively).
  
  
  
  A pharmacokinetic model including target-mediated elimination accurately described rituximab concentrations in CLL and showed that rituximab 'consumption' (target-mediated elimination) increases with increasing baseline antigen count on circulating B cells and in FCGR3A-158VV patients.
  
  
  
  NCT01370772.
authors: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.
authors: Mira
authors: M
authors: Tout
authors: Université de Montpellier, CNRS, UMR 5235, Montpellier, France.|Department of Hematology, CHU Montpellier, Montpellier, France.
authors: Anne-Laure
authors: AL
authors: Gagez
authors: Department of Hematology, Henri Becquerel Center, Rouen, France.
authors: Stéphane
authors: S
authors: Leprêtre
authors: Laboratory of Immunology, CHU de Tours, Tours, France.
authors: Valérie
authors: V
authors: Gouilleux-Gruart
authors: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.
authors: Nicolas
authors: N
authors: Azzopardi
authors: Department of Hematology, CHU de Reims, Reims, France.
authors: Alain
authors: A
authors: Delmer
authors: Department of Hematology, CHU Angers, Angers, France.
authors: Mélanie
authors: M
authors: Mercier
authors: Department of Hematology, CHU Toulouse, Toulouse, France.
authors: Loïc
authors: L
authors: Ysebaert
authors: Department of Hematology, CHG Le Mans, Le Mans, France.
authors: Kamel
authors: K
authors: Laribi
authors: Department of Hematology, CHG Pontoise, Pontoise, France.
authors: Hugo
authors: H
authors: Gonzalez
authors: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.|Laboratory of Pharmacology-Toxicology, CNRS, UMR 7292, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France.
authors: Gilles
authors: G
authors: Paintaud
authors: Université de Montpellier, CNRS, UMR 5235, Montpellier, France.|Department of Hematology, CHU Montpellier, Montpellier, France.
authors: Guillaume
authors: G
authors: Cartron
authors: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France. david.ternant@univ-tours.fr.|Laboratory of Pharmacology-Toxicology, CNRS, UMR 7292, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France. david.ternant@univ-tours.fr.
authors: David
authors: D
authors: Ternant
mesh_terms: D018951:Antigens, CD20 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000378:metabolism; D001830:Body Surface Area; D005260:Female; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics*; D000069283:Rituximab / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018951:Antigens, CD20; D000970:Antineoplastic Agents; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D000069283:Rituximab