Disposition of oral methotrexate in children with acute lymphoblastic leukemia and its relation to 6-mercaptopurine pharmacokinetics

✍ Scribed by Koren, Gideon ;Solh, Hassan ;Klein, Julia ;Soldin, Stephen J. ;Greenberg, Mark

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 444 KB
• Volume: 17
• Category: Article
• ISSN: 0098-1532
• DOI: 10.1002/mpo.2950170520

✦ Synopsis

We studied the disposition phannacokinetics of methotrexate (MTX) given orally to 16 children with acute lyrnphoblastic leukemia (ALL) and its relation to the pharrnacokinetics of 6-mercaptopurine (6MP) in the same children. There was an eightfold variability in area-under-concentration tirnecurve (AUC) of MTX achieved by the same dose.

Excellent correlation existed between peak concentrations and AUCo-_rj (r = 0.95, P < 0,001). Elimination T 1/ 2 was between 1.34 and 5 hours (mean 2.1620.23 hr, mean5SE). A weak correlation existed between AUC achieved by 1 m g h ' MTX and patients' age or body weight.

Weak but significant correlation existed between AUC achieved by 1 mg/rnL of MTX vs.

6MP (r = 0.54, P < 0.05). In 13/76 patients peak concentrations were achieved at 60 rnin-Utes. There was a significantly larger AUC of 6MP achieved by a standardized dose in longer therapy (> 15 rno) vs. short therapy (i 12 mo) (462?75 and 246558 ng~rnl-'~rnin.mg-'.m2, P < 0.025). No statistical differences in AUC of MTX were found between short and long ther-

The large interpatient variability in MTX pharmacokinetics supports the possibility that differences in absorption and/or clearance of the drug may affect the clinical response. Because of the excellent correlation between peak and AUC of MTX, and because 3 rneasurernents, at 30, 60, and 90 minutes will almost invariably identify the peak, this measurement can be used to estimate AUC for purpose of correlation with clinical outcome. apy.