Age-related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma

Plasma methotrexate (MTX) concentrations were determined in 52 patients after 409 infusions of high-dose (HD) (50-250 mg/kg) MTX with citrovorum factor (CF) rescue. In addition, detailed pharmacokinetic studies were conducted in nine of these patients. Plasma drug levels were compared at 6, 24, 48, and 72 hours from the start of MTX infusions in four different age groups (less than or equal to 10, 11-14, 15-17, and greater than or equal to 18 years of age). At the same drug dose, the younger patients had lower plasma MTX levels than the older patients at 6 and 24 hours. This difference increased in significance with increasing MTX dose. However, MTX plasma levels became similar at 48 and 72 hours, regardless of age. The half-life for the first phase of biphasic MTX clearance in children was shorter than that in adults. In addition, the urinary excretion of MTX was faster in younger children at all doses. The younger patients had a greater apparent volume of distribution of MTX after HD infusion. These results indicate that the age-dependent pharmacokinetics can be attributed to greater distribution and elimination of MTX in the younger patients. The potential difference in the metabolism of MTX between children and adults is currently under investigation. Our observations suggest that age exerts a dominant effect on the pharmacokinetics of HD-MTX.