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

Author:

Gebhard Anna,Lilienthal Patrick,Metzler Markus,Rauh Manfred,Sager Sebastian,Schmiegelow Kjeld,Toksvang Linea Natalie,Zierk Jakob

Abstract

AbstractIn 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.

Funder

The Carl and Ellen Hertz Foundation

The Children’s Cancer Foundation of Sweden

The Danish Cancer Society

The JPC Foundation

The Lundbeck Foundation

The Minister Erna Hamilton Foundation

The Nordic Cancer Union

United States National Institutes of Health

Deutsche Forschungsgemeinschaft

Otto-von-Guericke-Universität Magdeburg

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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