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

Gebhard A, Lilienthal P, Metzler M, Rauh M, Sager S, Schmiegelow K, Toksvang LN, Zierk J (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Scientific Reports Nature Publishing Group: Open Access Journals - Option B

Book Volume: 13

Article Number: 11749

Journal Issue: 1

DOI: 10.1038/s41598-023-38414-0

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.

Authors with CRIS profile

Markus Metzler Professur für Kinder- und Jugendmedizin mit dem Schwerpunkt Pädiatrische Onkologie und Hämatologie Manfred Rauh Department of Paediatrics and Adolescent Medicine Jakob Zierk Department of Paediatrics and Adolescent Medicine

Involved external institutions

Rigshospitalet DK Denmark (DK) Otto-von-Guericke-Universität Magdeburg DE Germany (DE)

How to cite

APA:

Gebhard, A., Lilienthal, P., Metzler, M., Rauh, M., Sager, S., Schmiegelow, K.,... Zierk, J. (2023). Pharmacokinetic–pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia. Scientific Reports, 13(1). https://doi.org/10.1038/s41598-023-38414-0

MLA:

Gebhard, Anna, et al. "Pharmacokinetic–pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia." Scientific Reports 13.1 (2023).

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