Interindividual variability in the concentration–effect relationship of antilymphocyte globulins—a possible influence of FcγRIIIa genetic polymorphism
Interindividual variability in the concentration–effect relationship of antilymphocyte globulins—a possible influence of FcγRIIIa genetic polymorphism
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抗淋巴细胞球蛋白浓度效应关系的个体差异——FcγRIIIa基因多态性的可能影响
DOI：
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
G. Paintaud
中科院分区：
文献类型：
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作者：
D. Ternant;M. Büchler;M. Bénéton;G. Alvan;M. Ohresser;G. Touchard;B. D. Ligny;O. Toupance;H. Watier;Y. Lebranchu;G. Paintaud
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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 T1/2-α and T1/2-β-values were 1.3 and 25 days, respectively. The concentration of ALG leading to a 50% inhibition of lymphocyte input (IC50) 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.
影响因子：
45.3
作者：
Weng, WK;Levy, R
通讯作者：
Levy, R