Pharmacokinetics of high-dose methotrexate in infants aged less than 12 months treated for aggressive brain tumors

In infants aged less than 12 months, there are few data on pharmacokinetics of high-dose methotrexate (MTX) for brain tumors at the dose of 8 g/m². Consolidated knowledges are present only with the dose of 5 g/m² in acute lymphoblastic leukemia.

We collected data on 8 infants at the time of their first treatment with high-dose MTX, 8 g/m², to evaluate the pharmacokinetic profile. All children had a dose adjustment with a weight-based prescription (1 m² = 30 kg).

The median age was 4.5 months (range 0–9). The median weight was 5.63 kg (range 3.12–9.0). The median steady-state MTX concentration at the end of 6-hr infusion was 486 µM/L (range 227–790). The median systemic MTX clearance was 4.14 L/h/m² (range 1.98–9.35). The median MTX concentration after 24 h from the beginning of infusion was 3.29 µM/L (range 1.14–100.44). Three (37.5 %) patients had a delayed elimination of MTX (delayed early, delayed late, or total delayed: one for each). These altered elimination occurred principally in children weighing less than 4 kg (p: 0.0179). Moreover, a systemic MTX clearance at the end of infusion minor than 3 L/h/m² can predict a delayed elimination (p: 0.0179). Patients with altered elimination underwent rescue measures (leucovorin supplement and/or exchange transfusion).

Our data suggest that a higher dose of MTX for the treatment of aggressive brain tumors in early infants had an acceptable pharmacokinetic profile. Greater attention must be used in the treatment of children weighing less than 4 kg.