title: Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients.
abstract: Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients.
  
  
  
  In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis.
  
  
  
  A two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7 l and 0.56 l day-1, respectively. Distribution and elimination half-lives were 0.9 days and 17.3 days, respectively. As expected, the central volume of distribution increased with body surface area (P = 0.012) and was higher in male than in female (P = 0.004). We found that the elimination rate constant (k10) increased with CD19+ count (P = 0.00022) and IgG concentration (P = 7.4 × 10-8), and that k10decreased with time (P = 0.00015), partly explained by a change in target-antigen amount.
  
  
  
  The association between CD19+ count and k10may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k10may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Service de Médecine Interne, CHRU de Tours, Tours, France.
authors.forename: Bertrand
authors.identifier: 0000-0002-0334-9553
authors.initials: B
authors.lastname: Lioger
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.
authors.forename: Soujanya Ratna
authors.initials: SR
authors.lastname: Edupuganti
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Service de Rhumatologie, CHRU de Tours, Tours, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Mulleman
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Laboratoire de Pharmacologie-Toxicologie, CHRU de Tours, Tours, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Passot
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Laboratoire de Pharmacologie-Toxicologie, CHRU de Tours, Tours, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Desvignes
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Service de Pharmacologie Clinique, CHRU de Tours, Tours, France.
authors.forename: Théodora
authors.initials: T
authors.lastname: Bejan-Angoulvant
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Laboratoire d'Immunologie, CHRU de Tours, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Thibault
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Laboratoire d'Immunologie, CHRU de Tours, Tours, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Service de Rhumatologie, CHRU de Tours, Tours, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mélet
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Laboratoire de Pharmacologie-Toxicologie, CHRU de Tours, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.affiliation: CNRS, GICC UMR 7292, Université François-Rabelais de Tours, Tours, France.|Laboratoire de Pharmacologie-Toxicologie, CHRU de Tours, Tours, France.
authors.forename: David
authors.initials: D
authors.lastname: Ternant
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018941:Antigens, CD19 / Q000378:metabolism; D018951:Antigens, CD20 / Q000097:blood* / Q000378:metabolism; D018501:Antirheumatic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D001402:B-Lymphocytes / Q000378:metabolism*; D001830:Body Surface Area; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012737:Sex Factors
chemical_list: D018941:Antigens, CD19; D018951:Antigens, CD20; D018501:Antirheumatic Agents; C000604811:CD19 molecule, human; D007074:Immunoglobulin G; D000069283:Rituximab
keywords: elimination rate constant; immunoglobulin; pharmacokinetics; rheumatoid arthritis; rituximab