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Clin Pharmacokinet. 2019 Jul;58(7):899-910. doi: 10.1007/s40262-018-00734-0.

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.

Author information

1
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, CB #7569, Chapel Hill, NC, 27599-7569, USA.
2
University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
3
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., Kenilworth, NJ, USA.
4
Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, TX, USA.
5
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, CB #7569, Chapel Hill, NC, 27599-7569, USA. daniel.gonzalez@unc.edu.

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.

PMID:
30810947
PMCID:
PMC6658326
[Available on 2020-07-01]
DOI:
10.1007/s40262-018-00734-0

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