title: Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia.
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.
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary. csordaskatalin@gmail.com
authors.forename: Katalin
authors.initials: K
authors.lastname: Csordas
authors.forename: Marta
authors.initials: M
authors.lastname: Hegyi
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Eipel
authors.forename: Judit
authors.initials: J
authors.lastname: Muller
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Erdelyi
authors.forename: Gabor T
authors.initials: GT
authors.lastname: Kovacs
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008727:Methotrexate / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; C011864:7-hydroxymethotrexate; D008727:Methotrexate