Pharmacokinetics and toxicity of frequent intermediate dose methotrexate infusions

Serum methotrexate (MTX) levels were measured in 12 children (ages 2-18 years) who received a total of 56 24-h infusions of intermediate-dose methotrexate (500 mg/m2) at 1- to 3-week intervals. Mean peak serum MTX concentration 1/2 h following a bolus of 167 mg/m2 MTX (1/3 total dose) was 25.9 X 10(-6) M, mean plateau serum MTX concentration was 7 X 10(-6) M (over 8-24 h), and mean MTX clearance was 74 ml/min/m2. No significant changes in these values were noted with increasing number of infusions, suggesting that no metabolic adaptation occurred in the manner in which the body handled the MTX when it was given repeatedly in this fashion. However, adolescent patients (greater than or equal to 15 years) demonstrated a trend toward increased MTX clearance and decreased serum MTX concentration with greater than or equal to 5 infusions. In general, toxicity was minimal and did not increase with an increasing number of infusions. Significant toxicity was found only in adolescent patients, in spite of no documented difference in either MTX serum concentrations or clearance rates between adolescent and preadolescent patients.