INTERACTION BETWEEN TRIMETHOPRIM-SULFAMETHOXAZOLE AND METHOTREXATE IN CHILDREN WITH LEUKEMIA

Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean ±SD) 37.4±11% without TMP-SMX to 52.2±6.4% with TMP-SMX (p<0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5±4 to 7.6±1.5 ml/kg/min; p<0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1±6.8 to 5.6±2.4 ml/kg/min; p<0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r=0.91; p<0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs. © 1990 Mosby-Year Book, Inc.