Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis

• Published in: British journal of clinical pharmacology Vol. 73; no. 1; pp. 55 - 65
• Main Authors: Ternant, David, Mulleman, Denis, Lauféron, Francine, Vignault, Céline, Ducourau, Emilie, Wendling, Daniel, Goupille, Philippe, Paintaud, Gilles
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2012; Blackwell; Blackwell Science Inc
• Subjects: Adult; ankylosing spondylitis; Anti-Inflammatory Agents - pharmacokinetics; Antibodies, Monoclonal - pharmacokinetics; Antirheumatic Agents - pharmacology; Biological and medical sciences; Diseases of the osteoarticular system; Diseases of the spine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Inflammatory joint diseases; Infliximab; Male; Medical sciences; methotrexate; Methotrexate - pharmacology; Middle Aged; Models, Theoretical; Pharmacokinetics; Pharmacology. Drug treatments; Prospective Studies; Spondylitis, Ankylosing - drug therapy; Spondylitis, Ankylosing - metabolism; Treatment Outcome; Antineoplastic agent; Pharmacokinetic pharmacodynamic relationship; Cytokine; Diseases of the osteoarticular system; Antipsoriatic agent; Inflammatory joint disease; Monoclonal antibody; Spine disease; Anti-Tumor Necrosis Factor-alpha; Antifolate; Spondylarthropathy; Immunomodulator; Chronic; Antimetabolic; Infliximab; Anticytokine; Immunosuppressive agent; Methotrexate; Pharmacokinetics; Tumor necrosis factor α; Ankylosing spondylitis
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/j.1365-2125.2011.04050.x

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. AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.