title: Methotrexate polyglutamation in relation to infliximab pharmacokinetics in rheumatoid arthritis.
abstract: OBJECTIVE
  The combination of methotrexate (MTX) with infliximab can modify infliximab pharmacokinetics and lower the incidence of antibodies against infliximab (ATIs). We hypothesised that the pharmacokinetic interaction between MTX and infliximab is related to activation of MTX to immunosuppressive MTX polyglutamates (MTXPGs).
  
  
  METHODS
  Adult patients with rheumatoid arthritis receiving weekly MTX with infliximab for more than 3 months were enrolled in a cross-sectional study. Blood was collected at trough before the infusion of infliximab. Red blood cell (RBC) MTXPGs were measured using liquid chromatography, and circulating levels of infliximab were measured using a cell-based assay. ATIs were measured using enzyme immunoassays. Statistical analyses consisted of multiple regression and Wilcoxon tests.
  
  
  RESULTS
  In the 61 patients enrolled in the study, ATIs were detected in 11 (18%). Regression analyses revealed that lower infliximab levels (median 3.3 µg/ml) were associated with the presence of ATIs and lower RBC MTXPG levels (median 28 nmol/l) (p<0.05). Logistic regression revealed that RBC MTXPG levels above 25 nmol/l were associated with a 4.7-fold lower likelihood of having ATIs (OR=4.7; 95% CI 1.1 to 20.8; p=0.02). None of the 12 patients with RBC MTXPG levels above 50 nmol/l tested positive for ATIs.
  
  
  CONCLUSIONS
  These hypothesis-generating data indicate that MTXPGs are associated with infliximab pharmacokinetics and ATI formation.
authors.affiliation: R&D Department, Exagen Diagnostics, Vista, California 92081, USA. tdervieux@exagen.com
authors.forename: Thierry
authors.initials: T
authors.lastname: Dervieux
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Alan
authors.initials: A
authors.lastname: Kivitz
authors.forename: Joel M
authors.initials: JM
authors.lastname: Kremer
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D018501:Antirheumatic Agents / Q000276:immunology / Q000493:pharmacokinetics*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D002853:Chromatography, Liquid; D003430:Cross-Sectional Studies; D004347:Drug Interactions / Q000276:immunology; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008875:Middle Aged; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018501:Antirheumatic Agents; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D000069285:Infliximab; D008727:Methotrexate