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Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia
G Ferrazzini1, J Klein, H Sulh
1Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario, Canada.
Abstract:
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 less than 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 less than 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 less than 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 less than 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.
Insights
Trimethoprim-sulfamethoxazole (TMP-SMX) increases methotrexate (MTX) exposure in children with leukemia. This drug interaction, driven by altered protein binding and renal clearance, may explain TMP-SMX-induced myelotoxicity.
Area of Science:
- Pharmacology
- Oncology
- Clinical Pharmacy
Background:
- Trimethoprim-sulfamethoxazole (TMP-SMX) is known to cause neutropenia in children undergoing leukemia treatment.
- Methotrexate (MTX) is a critical antileukemia agent whose accumulation can lead to toxicity.
Purpose of the Study:
- To investigate the pharmacokinetic interaction between TMP-SMX and MTX in pediatric leukemia patients.
- To determine if TMP-SMX causes MTX accumulation by affecting its protein binding and clearance.
Main Methods:
- Studied the pharmacokinetics of intravenous and oral MTX in nine children with acute lymphoblastic leukemia.
- Administered MTX both with and without TMP-SMX to assess drug interaction effects.
- Measured free MTX fraction, plasma clearance, renal clearance, and elimination half-life.
Main Results:
- TMP-SMX significantly increased the free fraction of MTX (from 37.4% to 52.2%).
- Clearance of free MTX and renal clearance of free MTX significantly decreased (p < 0.05).
- A mean 66% increase in systemic exposure to MTX was observed with coadministration.
Conclusions:
- TMP-SMX alters MTX protein binding and reduces its renal clearance, leading to increased systemic exposure.
- This pharmacokinetic interaction likely contributes to the myelotoxicity observed when TMP-SMX and MTX are used concurrently in pediatric leukemia patients.