Reduced Citrovorum Factor Rescue for High-Dose Methotrexate Therapy in Childhood Malignancies

Abstract
Clinical toxicities and pharmacokinetics of methotrexate (MTX), associated with reduced citrovorum factor (CF) neutralization, were studied on 279 infusions in 25 children with various malignancies. MTX, at 1000-8400 mg/m2, was infused during 6-24 h with multiple schedules of reduced CF rescue. Plasma MTX levels ranged from 7.0 .times. 10-5 to 7.0 .times. 10-4 M during MTX infusion. The levels declined rapidly with a 2-phase elimination pattern (t1/2 half life = 1.2-2.5 h, t1/2 = 18-32 h). The folate level in the plasma ranged from 5 .times. 10-7 M to 1.4 .times. 10-6 M when CF was administered every 6 h or every 3 h, respectively. Limited bone marrow suppression was seen in only 7% of infusions, with moderate elevation of GOT [aspartate transaminase] and GPT [alanine transaminase] in 20% of infusions and stomatitis in only 2.6% of infusions, despite reduction in the total dose of CF from 225 mg-105 mg and despite delaying CF initiation from 9 h-36 h after the start of MTX infusion.