TY - JOUR
T1 - Disposition of oral methotrexate in children with acute lymphoblastic leukemia and its relation to 6‐mercaptopurine pharmacokinetics
AU - Koren, Gideon
AU - Solh, Hassan
AU - Klein, Julia
AU - Soldin, Stephen J.
AU - Greenberg, Mark
PY - 1989
Y1 - 1989
N2 - We studied the disposition pharmacokinetics of methotrexate (MTX) given orally to 16 children with acute lymphoblastic leukemia (ALL) and its relation to the pharmacokinetics of 6‐mercaptopurine (6MP) in the same children. There was an eightfold variability in area‐under‐concentration timecurve (AUC) of MTX achieved by the same dose. Excellent correlation existed between peak concentrations and AUC0 → ∞ (r = 0.95, P < 0.001). Elimination T 1/2 was between 1.34 and 5 hours (mean 2.16±0.23 hr, mean±SE). A weak correlation existed between AUC achieved by 1 mg/m2 MTX and patients' age or body weight. Weak but significant correlation existed between AUC achieved by 1 mg/m2 of MTX vs. 6MP (r = 0.54, P < 0.05). In 13/16 patients peak concentrations were achieved at 60 minutes. There was a significantly larger AUC of 6MP achieved by a standardized dose in longer therapy (> 15 mo) vs. short therapy (< 12 mo) (462±75 and 246±58 ng·ml−1 · min·mg−2, P < 0.025). No statistical differences in AUC of MTX were found between short and long therapy. 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 measurements, 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.
AB - We studied the disposition pharmacokinetics of methotrexate (MTX) given orally to 16 children with acute lymphoblastic leukemia (ALL) and its relation to the pharmacokinetics of 6‐mercaptopurine (6MP) in the same children. There was an eightfold variability in area‐under‐concentration timecurve (AUC) of MTX achieved by the same dose. Excellent correlation existed between peak concentrations and AUC0 → ∞ (r = 0.95, P < 0.001). Elimination T 1/2 was between 1.34 and 5 hours (mean 2.16±0.23 hr, mean±SE). A weak correlation existed between AUC achieved by 1 mg/m2 MTX and patients' age or body weight. Weak but significant correlation existed between AUC achieved by 1 mg/m2 of MTX vs. 6MP (r = 0.54, P < 0.05). In 13/16 patients peak concentrations were achieved at 60 minutes. There was a significantly larger AUC of 6MP achieved by a standardized dose in longer therapy (> 15 mo) vs. short therapy (< 12 mo) (462±75 and 246±58 ng·ml−1 · min·mg−2, P < 0.025). No statistical differences in AUC of MTX were found between short and long therapy. 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 measurements, 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.
KW - 6‐mercaptopurine
KW - acute leukemia
KW - methotrexate
UR - http://www.scopus.com/inward/record.url?scp=0024820035&partnerID=8YFLogxK
U2 - 10.1002/mpo.2950170520
DO - 10.1002/mpo.2950170520
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C2 - 2586358
AN - SCOPUS:0024820035
SN - 0098-1532
VL - 17
SP - 450
EP - 454
JO - Medical and Pediatric Oncology
JF - Medical and Pediatric Oncology
IS - 5-6
ER -