PHARMACOKINETICS OF HD-MTX IN INFANTS, CHILDREN, AND ADOLESCENTS WITHNON-B ACUTE LYMPHOBLASTIC-LEUKEMIA

A retrospective pharmacokinetic analysis was done of methotrexate seru m levels after high-dose treatment (HD-MTX, four cycles at two-week in tervals of 5 g/sq.1m. over 24 h i.v.) in children with non-B acute lym phoblastic leukemia (ALL) with the specific aim of seeking differences in patients of different ages, including infants under one year. A to tal of 122 children (seven infants aged 3 months-1 year, 26 children a ged 1-3 years, 68 children aged 3-10 years and 21 adolescents aged 10- 15 years) with normal liver and renal function, receiving consolidatio n therapy at the Pediatric Clinic of Monza between May 1988 and April 1992, were enrolled in this study. MTX was given as an intravenous inf usion in 24 h and serum concentrations were measured up to at least 72 h after the start of infusion by an enzyme immunoassay (TDX Abbot, Da llas, TX) in order to modulate folinic acid rescue.Pharmacokinetic ana lysis of MTX levels according to a two-compartment open model indicate d that, compared to all children up to 10 years old, in adolescents ol der than 10 years the drug reached higher concentrations in serum and was cleared at a lower rate. Steady-state levels and AUC were from 60% higher to more than double and the total clearance of the compound, e xpressed either per square meter surface area or per kg body weight, i n each cycle was significantly lower in adolescents >10 years of age, sometimes being only one-third of the clearance in infants (0.2 vs. 0. 6 1/h/kg and 6.6 vs. 10.7 1/h/sq.m.). The relationship between each ag e and systemic clearance was highly significant as measured by regress ion analysis. Methotrexate systemic clearance progressively decreased as a function of age. Subsequent treatments did not induce changes in MTX pharmacokinetics. These data suggest that the better tolerance of HD-MTX in children may have a pharmacokinetic basis. The faster elimin ation of MTX in infants, who usually show the worst prognosis, suggest s that full doses could be safely used in order to maximize the antile ukemic effect without a high risk of toxicity. (C) 1995 Wiley-Liss, In c.