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Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis.

ABSTRACT: Infliximab, an anti-tumour necrosis factor?? 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.Twenty-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.A 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.Using 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.

SUBMITTER: Ternant D

PROVIDER: S-EPMC3248256 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis.

Ternant David D Mulleman Denis D Lauféron Francine F Vignault Céline C Ducourau Emilie E Wendling Daniel D Goupille Philippe P Paintaud Gilles G

British journal of clinical pharmacology 20120101 1

<h4>Aims</h4>Infliximab, an anti-tumour necrosis factor α 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.<h4>Methods</h4>Twenty-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 ...[more]

PMID: 21692827

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Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.

Dataset Information

Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis.

Publications

Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis.

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