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      Pharmacokinetic–pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia

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          Abstract

          In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient. We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic–pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization.

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          Most cited references45

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          Acute Lymphoblastic Leukemia in Children.

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              Simplified calculation of body-surface area.

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                Author and article information

                Contributors
                anna.gebhard@ovgu.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                20 July 2023
                20 July 2023
                2023
                : 13
                : 11749
                Affiliations
                [1 ]GRID grid.5807.a, ISNI 0000 0001 1018 4307, MathOpt group, Institute of Mathematical Optimization, Faculty of Mathematics, , Otto von Guericke University Magdeburg, ; Magdeburg, Germany
                [2 ]GRID grid.411668.c, ISNI 0000 0000 9935 6525, Department of Pediatrics and Adolescent Medicine, , University Hospital Erlangen, ; Erlangen, Germany
                [3 ]GRID grid.475435.4, Department of Pediatrics and Adolescent Medicine, , University Hospital Rigshospitalet, ; Copenhagen, Denmark
                [4 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Institute of Clinical Medicine, Faculty of Medicine, , University of Copenhagen, ; Copenhagen, Denmark
                Article
                38414
                10.1038/s41598-023-38414-0
                10359452
                37474565
                274e0e73-9f5c-4450-8799-6749765a2645
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 March 2023
                : 7 July 2023
                Funding
                Funded by: The Carl and Ellen Hertz Foundation
                Funded by: The Children’s Cancer Foundation of Sweden
                Award ID: 53/91
                Award ID: 62/94
                Award ID: 72/96
                Award ID: 98/59
                Award Recipient :
                Funded by: The Danish Cancer Society
                Award ID: 91–048
                Award ID: 92–017
                Award ID: 95–100-28
                Award Recipient :
                Funded by: The JPC Foundation
                Funded by: The Lundbeck Foundation
                Award ID: 38/99
                Award Recipient :
                Funded by: The Minister Erna Hamilton Foundation
                Funded by: The Nordic Cancer Union
                Award ID: 56–9257
                Award ID: 56–100-03–9102
                Award Recipient :
                Funded by: United States National Institutes of Health
                Award ID: RO1-GM28157
                Award ID: RO1-GM35720
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: 462065145
                Award Recipient :
                Funded by: Otto-von-Guericke-Universität Magdeburg (3121)
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2023

                Uncategorized
                computational biology and bioinformatics,oncology
                Uncategorized
                computational biology and bioinformatics, oncology

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