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- Title
The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children's Oncology Group.
- Authors
Beechinor, Ryan J.; Thompson, Patrick A.; Hwang, Michael F.; Vargo, Ryan C.; Bomgaars, Lisa R.; Gerhart, Jacqueline G.; Dreyer, ZoAnn E.; Gonzalez, Daniel
- Abstract
<bold>Background: </bold>Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity.<bold>Objective: </bold>The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL.<bold>Methods: </bold>A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m2 intravenously for four cycles during weeks 4-12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization.<bold>Results: </bold>Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations.<bold>Conclusion: </bold>Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.
- Subjects
PREMATURE infants; LYMPHOBLASTIC leukemia; INFANTS; ACUTE leukemia; METHOTREXATE; PHARMACOKINETICS; ONCOLOGY; BIOLOGICAL models; RESEARCH; RESEARCH methodology; ANTINEOPLASTIC agents; EVALUATION research; MEDICAL cooperation; ANTIMETABOLITES; COMPARATIVE studies; RESEARCH funding
- Publication
Clinical Pharmacokinetics, 2019, Vol 58, Issue 7, p899
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-018-00734-0