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

Maria Luisa Garré, Mary V. Relling, David Kalwinsky, Richard Dodge, William R. Crom, Minnie Abromowitch, Ching Hon Pui, William E. Evans

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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 μmol/L, respectively, P=0.03). When a 42-hour MTX concentration of 0.5 μmol/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<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<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.

Original languageEnglish (US)
Pages (from-to)606-612
Number of pages7
JournalThe Journal of Pediatrics
Volume111
Issue number4
DOIs
Publication statusPublished - Oct 1987

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ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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