Pharmacokinetics of oral and subcutaneous methotrexate in red and white blood cells in patients with early rheumatoid arthritis: the methotrexate monitoring trial.

Abstract

To investigate the pharmacokinetics of methotrexate polyglutamate (MTX-PG) accumulation in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) in patients with early rheumatoid arthritis (RA) after oral and subcutaneous MTX treatment. In a clinical prospective cohort study (Methotrexate Monitoring study), newly diagnosed patients with RA were randomised for oral or subcutaneous MTX. At 1, 2, 3 and 6 months after therapy initiation, blood was collected and RBCs and PBMCs were isolated. MTX-PG_1-6 concentrations were determined by mass spectrometry methods using stable isotopes of MTX-PG_1-6 as internal standards. 43 patients (mean age: 58.5 years, 77% female) were included. PBMCs and RBCs revealed disparate pharmacokinetic profiles in both absolute MTX-PG accumulation levels and distribution profiles. Intracellular MTX-PG accumulation in PBMCs was significantly (p<0.001) 10-fold to 20-fold higher than RBCs at all time points, regardless of the administration route. MTX-PG distribution in PBMCs was composed of mostly MTX-PG₁ (PG₁>PG₂>PG₃). Remarkably, the distribution profile in PBMCs remained constant over 6 months. RBCs accumulated mainly MTX-PG₁ and lower levels of MTX-PG_2-5 at t=1 month. After 3 months, MTX-PG₃ was the main PG-moiety in RBCs, a profile retained after 6 months of MTX therapy. Subcutaneous MTX administration results in higher RBC drug levels than after oral administration, especially shortly after treatment initiation. This is the first study reporting disparate MTX-PG accumulation profiles in RBCs versus PBMCs in newly diagnosed patients with RA during 6 months oral or subcutaneous MTX administration. This analysis can contribute to improved MTX therapeutic drug monitoring for patients with RA. NTR 7149.