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Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group
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Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group
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Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group
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Journal Article
Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group
2017
Overview
Background and objectives
Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcγRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL.
Methods
Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance.
Results
Target-mediated elimination rate constant increased with the baseline CD20 count on circulating B cells (
p
= 0.00046) and in patients with the
FCGR3A
-158VV genotype (
p
= 0.0016). Physiologic elimination of antigen was lower in the Binet C disease stage (
p
= 0.00018). The effects of these covariates on rituximab concentrations were mainly visible at the beginning of treatment. Body surface area also increased central and peripheral volumes of distribution (
p
= 1.3 × 10
−5
and 0.0015, respectively).
Conclusions
A pharmacokinetic model including target-mediated elimination accurately described rituximab concentrations in CLL and showed that rituximab ‘consumption’ (target-mediated elimination) increases with increasing baseline antigen count on circulating B cells and in
FCGR3A
-158VV patients.
Clinical trial registration: NCT01370772.
Publisher
Springer International Publishing,Springer Nature B.V,Springer Verlag
Subject
/ Antineoplastic Agents - blood
/ Antineoplastic Agents - pharmacokinetics
/ Antineoplastic Agents - pharmacology
/ Antineoplastic Agents - therapeutic use
/ Female
/ Genotype
/ Humans
/ Leukemia
/ Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
/ Leukemia, Lymphocytic, Chronic, B-Cell - genetics
/ Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
/ Lymphoma
/ Male
/ Medicine
/ Rituximab - pharmacokinetics
/ Studies
