TY - JOUR
T1 - Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia
AU - Ferrazzini, Gianmario
AU - Klein, Julla
AU - Sulh, Hassan
AU - Chung, Derrick
AU - Griesbrecht, Esther
AU - Koren, Gideon
N1 - Funding Information:
Maintenance treatment of acute lymphoblastic leukemia includes administration of methotrexate, either orally or intravenously, for several years. 1 A combination of trimethoprim and sulfamethoxazole is also administered during maintenance therapy to prevent nosocomial infections Supported by grant No. 8544, from the Medical Research Council of Canada, and by the Leukemia Research Fund, Toronto; Dr. Ferrazzini supported by the Societe suisse de Pharmacologic Clinique et Taxieologie, the Schweizer National Fond ffir Forsehung, Zugerliga Ftir Krebsbekaempfung, Bristol Meyers, SA, and Hoffmann-La Roche. Submitted for publication March 13, 1990; accepted May 21, 1990. Reprint requests: Gideon Koren, MD, Division of Clinical Pharmacology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1XS, Canada. *Career Scientist at the Ontario Ministry of Health. 9/'25/22549 secondary to chemotherapy-induced immunosuppression. It has been recognized that TMP-SMX causes neutropenia in patients with acute lymphoblastic leukemia2; however, this phenomenon was attributed to the direct effect of TMP.SMX. 3-6 We investigated the possibility that pharmacokinetic interaction between MTX and TMP-SMX causes accumula-
PY - 1990/11
Y1 - 1990/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/0025094392
U2 - 10.1016/S0022-3476(05)83351-7
DO - 10.1016/S0022-3476(05)83351-7
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C2 - 2231218
AN - SCOPUS:0025094392
SN - 0022-3476
VL - 117
SP - 823
EP - 826
JO - Journal of Pediatrics
JF - Journal of Pediatrics
IS - 5
ER -