Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments
Open Access
- 13 June 2013
- journal article
- research article
- Published by Springer Nature in Cancer Chemotherapy and Pharmacology
- Vol. 72 (2), 369-378
- https://doi.org/10.1007/s00280-013-2206-x
Abstract
Purpose It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments. Methods In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual’s previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 μM (approximately 2.5 or 5 g/m2/day) for low- and standard-/high-risk patients, respectively. Results Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3–4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003). Conclusions Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.Keywords
This publication has 41 references indexed in Scilit:
- Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)Blood, 2011
- Shortening Infusion Time for High-Dose Methotrexate Alters Antileukemic Effects: A Randomized Prospective Clinical TrialJournal of Clinical Oncology, 2011
- Evaluating Performance of a Decision Support System to Improve Methotrexate Pharmacotherapy in Children and Young Adults With CancerTherapeutic Drug Monitoring, 2011
- Long-term results of the children's cancer group studies for childhood acute lymphoblastic leukemia 1983–2002: A Children's Oncology Group ReportLeukemia, 2009
- Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemiaLeukemia, 2009
- Treating Childhood Acute Lymphoblastic Leukemia without Cranial IrradiationNew England Journal of Medicine, 2009
- Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201Blood, 2007
- Understanding and Managing Methotrexate NephrotoxicityThe Oncologist, 2006
- Population Pharmacokinetics of High-Dose Methotrexate in Children with Acute Lymphoblastic LeukaemiaClinical Pharmacokinetics, 2006
- Use of Plasma Pharmacokinetics to Predict and Prevent Methotrexate ToxicityNew England Journal of Medicine, 1977