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Open Access 01-12-2021 | Pharmacokinetics | Research

Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

Authors: Usman Arshad, Max Taubert, Tamina Seeger-Nukpezah, Sami Ullah, Kirsten C. Spindeldreier, Ulrich Jaehde, Michael Hallek, Uwe Fuhr, Jörg Janne Vehreschild, Carolin Jakob

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies.

Methods

We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens.

Results

Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h^− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall.

Conclusion

A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

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Title: Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients
Authors: Usman Arshad
Max Taubert
Tamina Seeger-Nukpezah
Sami Ullah
Kirsten C. Spindeldreier
Ulrich Jaehde
Michael Hallek
Uwe Fuhr
Jörg Janne Vehreschild
Carolin Jakob
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Pharmacokinetics
Methotrexate
Methotrexate
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08443-x

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Abstract

Background

Methods

Results

Conclusion

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