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Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia.
- Source :
-
Anti-cancer drugs [Anticancer Drugs] 2013 Feb; Vol. 24 (2), pp. 189-97. - Publication Year :
- 2013
-
Abstract
- We carried out a detailed comparative study of the pharmacokinetics and toxicity of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) after high-dose intravenous methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL). Overall, 65 children were treated with 5 g/m2/24 h MTX and 88 children were treated with 2 g/m2/24 h MTX according to ALL-BFM 95 and ALL IC-BFM 2002 protocols (mean age: 6.4 years, range 1.0-17.9 years). A total of 583 HD-MTX courses were analyzed. Serum MTX and 7-OH-MTX levels were measured at 24, 36, and 48 h, and cerebrospinal fluid (CSF) MTX levels were determined 24 h after the initiation of the infusion. The area under the concentration-time curve was calculated. Hepatotoxicity, nephrotoxicity, and bone marrow toxicity were estimated by routine laboratory tests. We investigated pharmacokinetics and toxicity in distinct age groups (< 6 and > 14 years). 5 g/m2/24 h treatments resulted in higher serum and CSF MTX and 7-OH-MTX levels (P < 0.05). The CSF penetration rate of MTX was independent of the MTX dose [2.3% (95% confidence interval: 1.7-2.5%) vs. 2.8% (95% confidence interval: 2.4-3%)]. The CSF MTX concentration was correlated with the 24 h MTX serum level (r = 0.38, P < 0.0001). Repeated treatments did not alter MTX or 7-OH-MTX levels. 7-OH-MTX levels were correlated with nephrotoxicity (r = 0.36, P < 0.0001). Higher MTX levels and toxicity occurred more frequently in children aged older than 14 years (P < 0.05). Therapeutic serum and CSF MTX concentrations can be achieved more reliably with 5 g/m2/24 h treatments. To predict the development of toxicity, monitoring of the level of the 7-OH-MTX is useful. Monitoring of pharmacokinetics is essential to prevent the development of severe adverse events in adolescents.
- Subjects :
- Adolescent
Antimetabolites, Antineoplastic blood
Antimetabolites, Antineoplastic cerebrospinal fluid
Area Under Curve
Cerebrospinal Fluid metabolism
Child
Child, Preschool
Dose-Response Relationship, Drug
Humans
Infant
Infusions, Intravenous
Methotrexate blood
Methotrexate cerebrospinal fluid
Precursor Cell Lymphoblastic Leukemia-Lymphoma blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma cerebrospinal fluid
Antimetabolites, Antineoplastic adverse effects
Antimetabolites, Antineoplastic pharmacokinetics
Methotrexate adverse effects
Methotrexate analogs & derivatives
Methotrexate pharmacokinetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1473-5741
- Volume :
- 24
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Anti-cancer drugs
- Publication Type :
- Academic Journal
- Accession number :
- 23187460
- Full Text :
- https://doi.org/10.1097/CAD.0b013e32835b8662