Prospective evaluation of serum methotrexate pharmacokinetics following intrathecal methotrexate in acute lymphoblastic leukaemia

Serum methotrexate (MTX) monitoring is standard following high-dose intravenous MTX but lacks established reference values after intrathecal (IT) administration, limiting interpretation during suspected IT-MTX toxicity or overdose. We prospectively evaluated serum MTX pharmacokinetics following 124 IT-MTX doses administered to 44 children with acute lymphoblastic leukaemia (ALL) treated on contemporary protocols to establish reference serum concentrations and assess association with MTX-related neurotoxicity. Serum MTX concentrations were measured at 2-4 h (TP1), 24 h (TP2) and 48 h (TP3) after IT-MTX. Mean concentrations were 0.62 ± 0.56 μmol/L at TP1, 0.057 ± 0.039 μmol/L at TP2; by TP3, 82% of samples were below the lower limit of quantification. The apparent terminal half-life was 8.3 h. Serum concentrations varied modestly across treatment phases, with the highest TP1 concentrations during consolidation (p = 0.042) and the highest TP2 concentrations during delayed intensification (DI) (p = 0.009). MTX-related neurotoxicity occurred in 7 of 44 patients (16%) and was associated with age ≥10 years (p = 0.02), but not with serum MTX concentrations. These findings establish contemporary reference serum MTX concentrations following standard IT-MTX administration that may assist clinicians in interpreting unexpectedly elevated serum MTX levels during suspected overdose, medication error or severe toxicity.