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.

Reply to Prof Ian J. Cohen

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Regarding pharmacokinetics, Csordas et al [3] recently confirmed that CSF MTX concentration was correlated with the 24-h MTX serum level, but they also demonstrated that CSF penetration rate of MTX was independent of the MTX dose on a total of 583 HD-MTX courses analyzed.May all of these aspects justify a routinely invasive procedure and the relative deep sedation for these "early" infants?Regarding the second point raised by Cohen, the folinic acid rescue dose of 15 mg/m 2 is a standard quantity provided for different protocols of HD-MTX. Borsi et al [4] treating with HD-MTX up to 8 g/m 2 had previously evaluated the event-free survival of children receiving less or more than 15 mg/m 2 (75 mg/m 2 ) rescue in patients with acute lymphoblastic leukemia.

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“…Regarding pharmacokinetics, Csordas et al [3] recently confirmed that CSF MTX concentration was correlated with the 24-h MTX serum level, but they also demonstrated that CSF penetration rate of MTX was independent of the MTX dose on a total of 583 HD-MTX courses analyzed.…”

Effect of High Dose Methotrexate and Delayed Elimination on Myelotoxicity Progression in Children With Acute Lymphoblastic Leukemia

“…Theydocumented that the MTX levels at 42 h in patients with myelotoxicity were not different from patients without toxicity. Additionally, Csordas et al [33] did not find any correlation between myelotoxicity and the levels of serum MTX. However, other studies reported that there is a relationship between elevated serum MTX levels and hematologic toxicity [6] .…”

Pharmacokinetics and Bioequivalence of Methotrexate in Human Plasma Studied by Liquid Chromatography-Mass Spectrometry (LC-MS)

“…Its use in patients with brain tumors is primarily confined to primary central nervous system lymphoma (PCNSL), in which it is the cornerstone of chemotherapy (1). In addition to the clinical use of MTX, it is the subject of many preclinical investigations due to to its interesting pharmacological properties.…”

“…The mean results for the same sample analysis between our laboratory and two different test facilities were obtained, and the % difference between content measurements was calculated using the Equation 1: (1) [ (Highest value − Lowest value)…”