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Interindividual variability in the concentration–effect relationship of antilymphocyte globulins—a possible influence of FcγRIIIa genetic polymorphism
Author(s) -
Ternant David,
Büchler Matthias,
Bénéton Maud,
Alván Gunnar,
Ohresser Marc,
Touchard Guy,
Hurault de Ligny Bruno,
Toupance Olivier,
Watier Hervé,
Lebranchu Yvon,
Paintaud Gilles
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02967.x
Subject(s) - polymorphism (computer science) , globulin , immunology , genetics , biology , genotype , gene
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • There is interindividual variability in the antilymphocyte globulin (ALG) effect, but there is no pharmacokinetic–pharmacodynamic study of this subject. • In addition, a time dependence of the pharmacokinetics of some therapeutic antibodies has been described. • ALGs may partly act by antibody‐dependent cellular cytotoxicity (ADCC), but their mechanism of action in humans is not known. WHAT THIS STUDY ADDS • Horse ALG pharmacokinetics can be described using a two‐compartment model with time‐dependent central volume of distribution. • After an initial concentration‐independent lymphocyte depletion, the concentration–effect relationship can be described using a physiological indirect response model. • The genetic polymorphism of FcγRIIIa at position 158 may influence the ALG concentration–effect relationship and these polyclonal antibodies may therefore act by ADCC. AIMS 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 FcγRIIIa, 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 ‐α and T 1/2 ‐β‐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 FcγRIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC.