Pharmacokinetics of Oral Methotrexate in Patients With Rheumatoid Arthritis

Objective. There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu(1-5) is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu(1-5) in patients with RA commencing oral MTX, and the time for RBC MTXGlu(1-5) to become undetectable and the half-life of elimination of RBC MTXGlu(1-5) in patients ceasing treatment with oral MTX. Methods. Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu(1-5) concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method. Results. The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2,, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu(1), MTXGlu(2), MTXGlu(3), MTXGlu(4) and MTXGlu(5). The median half-life of accumulation for RBC MTXGlu(1-5) ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu(1), MTXGlu(2), MTXGlu(3), MTXGlu(4), and MTXGlu(5). The median half-life of elimination for RBC MTXGlu(1-5) ranged from 1.2 weeks to 4.3 weeks. Conclusion. There is wide interpatient variability of RBC MTXGlu(1-5) accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu(1-5) to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.