title: Interindividual variability in the concentration-effect relationship of antilymphocyte globulins - a possible influence of FcgammaRIIIa genetic polymorphism.
abstract: OBJECTIVE
  Polyclonal antilymphocyte globulins (ALGs) are currently used in transplantation, but the sources of interindividual variability of their effect are poorly understood. No pharmacokinetic-pharmacodynamic (PK-PD) study of ALG is available. Moreover, the genetic polymorphism of FcgammaRIIIa, a receptor for the Fc portion of immunoglobulins involved in antibody-dependent cellular cytotoxicity (ADCC), may influence their concentration-effect relationship.
  
  
  METHODS
  Fourteen kidney transplant patients treated by horse ALG were included in a prospective, noncomparative study. A population two-compartment PK model including a time dependence of the central volume of distribution was developed. Total lymphocyte count was used as biomarker of effect. Concentration-effect data were described using a physiological indirect response model, combining concentration-dependent and -independent inhibitions of lymphocyte input into the circulation. In addition, six kidney transplant patients in whom ALG concentrations were not available were included retrospectively. All patients were genotyped for FCGR3A.
  
  
  RESULTS
  Both the PK and the PK-PD model described the data satisfactorily and showed high interindividual variability. Asymptotic T(1/2)-alpha and T(1/2)-beta-values were 1.3 and 25 days, respectively. The concentration of ALG leading to a 50% inhibition of lymphocyte input (IC(50)) was lower in FCGR3A-V carriers than in FCGR3A-F/F patients (383 +/- 199 vs. 593 +/- 209 mg l(-1), P = 0.008).
  
  
  CONCLUSIONS
  This is the first description of the ALG effect on lymphocyte count using PK-PD modelling. Our results show that part of the variability in their concentration-effect relationship may be explained by FcgammaRIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC.
authors.affiliation: Université François Rabelais, Tours, UPRES EA 3853 Immuno-Pharmaco-Genetics of therapeutic Antibodies, Tours, France.
authors.forename: David
authors.initials: D
authors.lastname: Ternant
authors.forename: Matthias
authors.initials: M
authors.lastname: Büchler
authors.forename: Maud
authors.initials: M
authors.lastname: Bénéton
authors.forename: Gunnar
authors.initials: G
authors.lastname: Alván
authors.forename: Marc
authors.initials: M
authors.lastname: Ohresser
authors.forename: Guy
authors.initials: G
authors.lastname: Touchard
authors.forename: Bruno
authors.initials: B
authors.lastname: Hurault de Ligny
authors.forename: Olivier
authors.initials: O
authors.lastname: Toupance
authors.forename: Hervé
authors.initials: H
authors.lastname: Watier
authors.forename: Yvon
authors.initials: Y
authors.lastname: Lebranchu
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
mesh_terms: D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology*; D018655:Lymphocyte Count / Q000379:methods; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D017452:Receptors, IgG / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
chemical_list: D000961:Antilymphocyte Serum; D015415:Biomarkers; C496124:FCGR3A protein, human; D007166:Immunosuppressive Agents; D017452:Receptors, IgG