Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Infliximab pharmacokinetics in ankylosing spondylitis has been described but using sparce data.• A previous work suggests that infliximab concentrations influence clinical response in ankylosing spondylitis, but the infliximab concentration-effect relationship is not known in this disease.• Methotrexate was shown to influence infliximab pharmacokinetics in rheumatoid arthritis. WHAT THIS STUDY ADDS• This study is the first to describe infliximab pharmacokinetics in ankylosing arthritis using rich data.• The infliximab concentration explains only a small part of interindividual variability in the response of ankylosing arthritis patients.• Contrary to what is observed in rheumatoid arthritis, methotrexate influences neither infliximab pharmacokinetics nor concentration-response relationship in ankylosing spondylitis. AIMSInfliximab, an anti-tumour necrosis factor a monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases. The objective was to assess the influence of methotrexate on the variability of infliximab pharmacokinetics and concentration-effect relationship in axial ankylosing spondylitis (AAS) patients. METHODSTwenty-six patients with AAS were included in a prospective study. They were treated by infliximab 5 mg kg -1 infusions at weeks 0, 2, 6, 12 and 18. Infliximab concentrations were measured before, and 2 and 4 h after each infusion, and at each intermediate visit (weeks 1, 3, 4, 5, 8, 10 and 14). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at each visit. Infliximab pharmacokinetics was described using a two-compartment model with first-order distribution and elimination constants. A population approach was used. Infliximab pharmacodynamics was described using the area under the BASDAI curve. RESULTSA total of 507 blood samples and 329 BASDAI measurements were collected. The following pharmacokinetic parameters were obtained (interindividual coefficient of variation): volumes of distribution for the central compartment = 2.4 l (9.6%) and peripheral compartment = 1.8 l (26%), systemic clearance = 0.23 l day -1 (22%) and intercompartment clearance = 2.3 l day -1. Methotrexate influenced neither pharmacokinetic nor BASDAI variability. CONCLUSIONSUsing the present dosage, the clinical efficacy of infliximab is only weakly influenced by its serum concentrations. The results do not support the combination of methotrexate with infliximab in ankylosing spondylitis.

Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases

“…However, the addition of MTX was not found to have a significant influence on the pharmacokinetics of infliximab or variability of disease activity (Ternant et al, 2012). Furthermore, clinical efficacy only correlated weakly with serum levels of infliximab, whereas drug monitoring did not improve disease activity (Meric et al, 2011;Ternant et al, 2012). Therefore, the current data do not support the addition of MTX to infliximab or other TNF inhibitors in AS.…”

“…More recent studies indicated that up to 25% of SpA patients develop antibodies to infliximab and that these correlate with increased disease activity and discontinuation of therapy (Plasencia et al, 2012). However, the addition of MTX was not found to have a significant influence on the pharmacokinetics of infliximab or variability of disease activity (Ternant et al, 2012). Furthermore, clinical efficacy only correlated weakly with serum levels of infliximab, whereas drug monitoring did not improve disease activity (Meric et al, 2011;Ternant et al, 2012).…”

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

“…27 Since only trough concentrations were available, we used a one-compartment model. Because most studies used a 2-compartmental model to describe infliximab pharmacokinetics, [4][5][6][8][9][10]12,13 there is a potential risk of increased bias and decreased precision of PK parameter estimation. However, this limitation was reported for compounds with poorly known pharmacokinetics, which is not the case of infliximab.…”

“…Infliximab elimination half-life was reported to be »14 d on average, 16 but with lower values in RA patients without methotrexate (9 days), than in RA patients cotreated with methotrexate (13 days), 4 AS 5,6 and in IBD 9,11,13 patients (»14 d for both conditions) ( Table 1). The increase in infliximab clearance (CL) with pre-infusion CRP 4,11 suggests an influence of target-antigen burden on infliximab pharmacokinetics, the elimination increasing with the target-antigen quantity.…”

“…Despite the adjustment of dose based on patients' weight, large interindividual variability in infliximab serum concentrations is observed. [1][2][3] Infliximab pharmacokinetics has been analyzed in RA, 4 AS 5,6 and inflammatory bowel disease (IBD) [7][8][9][10][11][12] patients using population compartmental modeling. These studies showed that several individual characteristics such as body weight, [4][5][6]9,10,12,13 sex, 5,9,13 anti-drug antibodies, 14,15 cotreatment with methotrexate 4 or preinfusion C-reactive protein (CRP) 4 were related to infliximab pharmacokinetic parameters.…”