Pharmacokinetic and clinical studies of 24-h infusions of high-dose methotrexate

Summary

Cytocidal activity of a drug is dependent on both drug dosage and duration of exposure. In contrast to the ‘conventional’ 6-h infusion and in an attempt to improve its efficacy, the high-dose methotrexate therapeutic regimen was given over a 24-h period with 10% of the dose administered in the first hour. Citrovorum factor was initiated at hour 24 and continued for 72 h. Treatment was administered every 2–3 weeks. 57 infusions were performed in twelve patients aged 7–20 years (six with osteogenic sarcoma and six with acute lymphoblastic leukemia). Determinations of serum methotrexate levels revealed that the levels were dependent on the dose. Levels assayed at 24 h revealed the following results: 4.4±1.4x10^-5 molar with 4.5 g/m², 2.04±0.34x10^-4 molar with 7.5 g/m² and 4.59±0.80x10^-4 molar with 12.5 g/m². Major toxicity was myelosuppression in 12 of 57 patients. There were no responses. The study demonstrates that 24-h infusions of high-dose methotrexate can be tolerated every 2–3 weeks in patients without bone marrow involvement and levels of at least 10^-4 molar can be maintained during the infusion.