Methotrexate Concentration Levels in the Cerebrospinal Fluid During High-Dose Methotrexate Infusions: An Unreliable Prediction

In 25 children with lymphoid malignancies, 96 high-dose methotrexate infusions (3 g/m2) with a duration of 24 h have been administered as a part of the treatment schedule. A lumbar puncture was performed to apply methotrexate intrathecally. The moment of lumbar puncture during the infusion was chosen at different times. In 76 of the infusions the concentration of methotrexate in the cerebrospinal fluid and in plasma were determined just prior to the intrathecal administration. From the second to the eighth hour after the initiation of the infusion the concentration of methotrexate in the cerebrospinal fluid and in plasma were determined just prior to the intrathecal administration. From the second to the eighth hour after the initiation of the infusion the concentration of methotrexate in the cerebrospinal fluid appeared to be significantly lower than 16 or 24 h after the initiation of the infusion. Of all samples during the infusions, the plasma concentration varied a tenfold (2-20 X 10(-5) mol/L), but the cerebrospinal fluid concentration of methotrexate varied about a 300-fold (3.5-900 x 10(-8) mol/L). No correlation could be found between the plasma concentration of methotrexate and the cerebrospinal fluid concentration. It is concluded that the methotrexate concentration in the cerebrospinal fluid cannot be predicted by determining the plasma concentration. It takes at least 8 h of infusion before a steady-state concentration of methotrexate is reached in the cerebrospinal fluid. In high-dose methotrexate infusions without intrathecal therapy, the dose of 3 g/m2 is the minimum amount of methotrexate to reach the minimum therapeutic concentration 5 x 10(-7) mol/L) in the cerebrospinal fluid for the treatment of subclinical central nervous system invasion of malignant lymphoid cells. To maintain the minimum therapeutic concentration according to the CxT principle the duration of the infusion should be preferably longer than 24 h.