Pharmacokinetic study and Fcγ receptor gene analysis in two patients with rheumatoid arthritis controlled by low-dose infliximab

Abstract

The main aim of this study is to investigate the pharmacokinetics of infliximab and Fcgamma receptor (FcgammaR) polymorphism in two patients with rheumatoid arthritis (RA) who were well controlled by low-dose infliximab. A 57-year-old woman (Patient 1) and a 67-year-old woman (Patient 2) had active RA despite methotrexate and prednisolone treatments. They improved after the addition of infliximab (3 mg/kg), but developed pneumonia and sepsis, respectively. Although the infliximab doses were reduced to 1.5 mg/kg and 1 mg/kg, respectively, clinical improvements were maintained. Blood samples were obtained at 1 h after infliximab administration and at eight weeks (just before the next dose). The elimination half-life was determined by the serum concentration of infliximab. We also analyzed the polymorphisms of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB for the genomic DNA samples from the two patients and three controls. Amplification of the FcgammaR-genomic regions in allotype-specific polymerase chain reactions was used to distinguish the genotypes. Decresed clearance of infliximab was proven by a pharmacokinetic study of these patients under low-dose infliximab therapy. 131H/H (FcgammaRIIA) and 176F/F (FcgammaRIIIA) were detected in both patients. NA1/NA2 and NA2/NA2 (FcgammaRIIIB) were detected in Patients 1 and 2, respectively. These patients were well controlled over the long term by low-dose infliximab. The mechanism of the reduced clearance of infliximab might possibly be explained in part by the FcgammaR polymorphisms.

Effects of FCGRIIIa‐158V/F polymorphism on antibody‐dependent cellular cytotoxicity activity of adalimumab

“…Thus, since the V/V genotype has higher ADCC activity against mTNFα‐expressing cells than V/F and F/F genotypes, the clinical effect of TNF inhibitors to CD is high in the V/V genotype. However, sTNFα rather than mTNFα participates in the condition formation of RA and PsA, and the amount of the TNF inhibitor, which is possible to bind to sTNFα, is reduced by ADCC . Thus, since the F/F genotype has lower ADCC activity than V/V and V/F genotypes, the clinical effect of TNF inhibitors to RA and PsA is high in the F/F genotype.…”

Proinflammatory Cytokines Synergistically Enhance the Production of Chemokine Ligand 20 (CCL20) from Rheumatoid Fibroblast-like Synovial Cells in vitro and Serum CCL20 Is Reduced in vivo by Biologic Disease-modifying Antirheumatic Drugs

“…Thus, the result shown in Figure 2 is reasonable, and our data represent the first definitive result to be published. We can determine the serum concentration of infliximab or etanercept in the treated patients to be low compared with the concentrations used in the present in vitro study 24,25 . Our data suggest that the IL-6-eliciting signal amplifies the production of CCL20 by IL-1ß, TNF-α, and IL-17, the signals being transmitted through nuclear factor-κB (NF-κB) 22 .…”

Pharmacokinetics of Monoclonal Antibodies

“…Similar results were reported for cetuximab in colorectal cancer and rituximab in B‐cell lymphoma . For infliximab, the effect of the FcγR IIIa genotype was suggested to not only be limited to pharmacodynamic efficacy, but also to affect pharmacokinetics, with a reduced clearance for the F/F genotype . These data suggest that Fcγ polymorphisms may affect mAb disposition if ADCC is a major elimination pathway for a specific antibody drug, but may have little or no impact on exposure for those mAbs in which ADCC is only a minor or not a relevant clearance pathway.…”