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27.02.2019 | 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

Zeitschrift:
Clinical Pharmacokinetics
Autoren:
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.

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.

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Zusatzmaterial
Electronic Supplementary Fig. 1 Weight-normalized clearance values for all 71 infants versus (a) post-natal age and (b) treatment cycle. Each point represents the post hoc estimate for individual subject clearance at each treatment cycle. The gray horizontal line represents the median weight-normalized clearance of 0.273 L/h/kg (TIFF 150 kb)
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Electronic Supplementary Fig. 2 Final model visual predictive check of the first 72 h after dosing. A total of 44 points (7.2%) fell outside the 90% prediction interval. The dotted and solid lines represent the 5th, 50th, and 95th percentiles of the simulated data and observed data, respectively. Gray-shaded areas represent the 90% prediction interval. The x-axis represents the time after the start of the 24-h methotrexate infusion, and the y-axis represents plasma methotrexate concentrations on a log scale (TIFF 94 kb)
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