Mira Tout1, Anne-Laure Gagez2,3, Stéphane Leprêtre4, Valérie Gouilleux-Gruart5, Nicolas Azzopardi1, Alain Delmer6, Mélanie Mercier7, Loïc Ysebaert8, Kamel Laribi9, Hugo Gonzalez10, Gilles Paintaud1,11, Guillaume Cartron2,3, David Ternant12,13. 1. Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France. 2. Université de Montpellier, CNRS, UMR 5235, Montpellier, France. 3. Department of Hematology, CHU Montpellier, Montpellier, France. 4. Department of Hematology, Henri Becquerel Center, Rouen, France. 5. Laboratory of Immunology, CHU de Tours, Tours, France. 6. Department of Hematology, CHU de Reims, Reims, France. 7. Department of Hematology, CHU Angers, Angers, France. 8. Department of Hematology, CHU Toulouse, Toulouse, France. 9. Department of Hematology, CHG Le Mans, Le Mans, France. 10. Department of Hematology, CHG Pontoise, Pontoise, France. 11. Laboratory of Pharmacology-Toxicology, CNRS, UMR 7292, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France. 12. Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France. david.ternant@univ-tours.fr. 13. Laboratory of Pharmacology-Toxicology, CNRS, UMR 7292, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France. david.ternant@univ-tours.fr.
Abstract
BACKGROUND AND OBJECTIVES: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. METHODS: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. RESULTS: 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 × 10-5 and 0.0015, respectively). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: NCT01370772.
RCT Entities:
BACKGROUND AND OBJECTIVES: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. METHODS: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. RESULTS: 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 × 10-5 and 0.0015, respectively). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: NCT01370772.
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