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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 7/2019

01-07-2019 | Acute Lymphoblastic Leukemia | Original Research Article

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: Ryan J. Beechinor, Patrick A. Thompson, Michael F. Hwang, Ryan C. Vargo, Lisa R. Bomgaars, Jacqueline G. Gerhart, ZoAnn E. Dreyer, Daniel Gonzalez

Published in: Clinical Pharmacokinetics | Issue 7/2019

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Abstract

Background

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.

Objective

The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL.

Methods

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.

Results

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.

Conclusion

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.
Appendix
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Metadata
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
Ryan J. Beechinor
Patrick A. Thompson
Michael F. Hwang
Ryan C. Vargo
Lisa R. Bomgaars
Jacqueline G. Gerhart
ZoAnn E. Dreyer
Daniel Gonzalez
Publication date
01-07-2019
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 7/2019
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-018-00734-0

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