Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

✍ Scribed by Judith M. Dalrymple; Lisa K. Stamp; John L. O'Donnell; Peter T. Chapman; Mei Zhang; Murray L. Barclay

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 282 KB
• Volume: 58
• Category: Article
• ISSN: 0004-3591
• DOI: 10.1002/art.24034

✦ Synopsis

Abstract

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.