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EP34595
Abstract: 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 (Fig. 1). 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.Summary: 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. PK/PD parameters were calibrated against in vivo data for
single dosage regime of EPO (Fig. 2 and 3).
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 (Fig. 1). 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.Summary: 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. PK/PD parameters were calibrated against in vivo data for
single dosage regime of EPO (Fig. 2 and 3).
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