Human normal erythropoiesys stimulated by ESA

Erythropoiesis-stimulating agents (ESAs) enhance the red blood cells (RBC) formation by bone marrow. They are used to manage anemic states caused by chemotherapy, bleeding, bone marrow’s malfunctions. To predict the effect of pharmacological intervention on hematopoiesis-related clinical endpoints we propose the QSP model of erythropoiesis.


ODE model of erythropoiesis was constructed to comprehensively describe cell dynamics from hematopoietic stem cell to circulating RBC. The model includes variables corresponding to specific stages of cell development distinguished based on morphology and surface markers expression. Model processes are cell self-renewal, differentiation, proliferation, migration from bone marrow into circulation and cell death. Binding of erythropoietin (EPO) and stem cell factor (SCF) to cell-surface receptors regulates cell dynamics with feedback on the receptor expression modulated by interleukine-3 (IL-3). Hypoxia-Inducible Factor (HIF) stabilizers (Roxadustat, Desidustat, Daprodustat and Molidustat) included in the model prevent the degradation of HIF, thereby inducing synthesis of EPO mRNA. Upregulation of EPO contributes to a negative feedback on HIF degradation through increased hemoglobin production. Regulation effects of EPO were implemented via explicit description of EPO binding to its receptor followed by internalization leading to acceleration of cell proliferation and differentiation, and inhibition of apoptosis. The model was calibrated across published in vitro/in vivo data including cell expansion under growth factors and cytokines exposure in vitro, flow cytometry cell counting of bone marrow aspirates and clinical data of ESAs’ administration such as epoetins and HIF stabilizers. The QSP model was implemented in Heta language.

PK/PD simulator for Erythropoiesis-Stimulating Agents (ESA) Application for the prediction of erythropoietic readouts after ESA administration in healthy human

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