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27.02.2019 | Original Research Article | Ausgabe 7/2019

Clinical Pharmacokinetics 7/2019

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

Clinical Pharmacokinetics > Ausgabe 7/2019
Ryan J. Beechinor, Patrick A. Thompson, Michael F. Hwang, Ryan C. Vargo, Lisa R. Bomgaars, Jacqueline G. Gerhart, ZoAnn E. Dreyer, Daniel Gonzalez
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s40262-018-00734-0) contains supplementary material, which is available to authorized users.



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.


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


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.


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.


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.

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