Journal
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Volume 65, Issue 1, Pages 60-68Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1365-2125.2007.02967.x
Keywords
antilymphocyte serum; dose - response relationship; IgG receptors; kidney transplantation; pharmacogenetics; pharmacokinetics
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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 Fc gamma RIIIa, 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 (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 Fc gamma RIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC.
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