Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia

Abstract

Children with Down syndrome and acute lymphocytic leukemia (ALL) have poor tolerance to antineoplastic drugs, including methotrexate (MTX). We evaluated MTX pharmacokinetics and toxicity in five patients with Down syndrome and ALL who had received multiple high doses of MTX (1 g/m2). Three control patients without Down syndrome were matched to each case according to sex, race, age, and initial leukocyte count. Median MTX plasma concentrations, measured 42 hours after infusion, were significantly higher in patients with Down syndrome versus control patients (average 0.47 vs 0.24 mumol/L, respectively, P = 0.03). When a 42-hour MTX concentration of 0.5 mumol/L was used to identify patients at risk for toxicity, more courses were considered at high risk for toxicity among patients with Down syndrome (31 of 62, 50%) than in control patients (13 of 214, 6.1%, P less than 0.0001). The average MTX clearance was 64.1 mL/min/m2 in Down syndrome vs an average control value of 80.6 mL/min/m2 (P = 0.13). Toxicity after each high-dose MTX course was graded according to standardized criteria. Grades 2 through 4 gastrointestinal toxicity and grades 3 and 4 hematologic toxicity occurred more frequently in the patients with Down syndrome (36% and 13.4% of courses, respectively) vs the control patients (3.6% and 0.9% respectively, P less than 0.0001 for both). This higher frequency of toxicity occurred despite higher doses and prolonged duration of leucovorin given to all patients with Down syndrome. We conclude that altered MTX pharmacokinetics may contribute to the higher incidence of MTX-induced toxicity seen in patients with Down syndrome.