Effect of Missed Doses on the Therapeutic Effect of Methotrexate for Rheumatoid Arthritis: A Pharmacokinetic Modeling Study

Introduction: Patients rarely, if ever, take their medications exactly as prescribed. The extent to which missed doses interfere with a drug's therapeutic effect remains unclear. Methods: After weekly oral dosing of methotrexate (MTX) for rheumatoid arthritis, its polyglutamate derivatives (MTXglu) accumulate in red blood cells, where they are markers for the drug's therapeutic effectiveness. We used Medication Event Monitoring System data and pharmacokinetic modeling to analyze whether missing MTX doses causes the MTXglu level in red blood cells to fall below the range associated with the drug's clinical effect. Results: For patients initiating oral MTX, the threshold for clinical effectiveness and the steady state level were reached in medians of 6 weeks and 22 weeks, respectively. For patients at steady state who discontinued MTX, the MTXglu level fell below the therapeutic threshold after a median of 3 weeks. After initiating MTX, single missed doses did not cause a loss of therapeutic effect in the median patient if they occurred after 10 weeks, while runs of >= 3 consecutive missed doses did cause the MTXglu level to fall below the therapeutic threshold. Conclusion: While there is considerable variation between patients, pharmacokinetic modeling indicates that instances of isolated single missed doses of MTX typically will not cause polyglutamated methotrexate levels in red blood cells to fall below the range associated with the therapeutic effect. Runs of >= 3 consecutive missed doses, however, are typically expected to result in a loss of the therapeutic effect.