Stimulation of erythropoiesis with ESA or blood donation: QSP model Alexander Stepanov1, Galina Lebedeva2 1 InSysBio, Moscow, Russia; 2 InSysBio UK Ltd, Edinburgh, UK INTRODUCTION RESULTS: PK/PD of EPO RESULTS: PK/PD of dustats Erythropoiesis-stimulating agents (ESAs) enhance the red blood cells Regulation effects of EPO were implemented via explicit description of The response of clinical outcomes such as reticulocytes count and (RBC) formation by bone marrow. They are used to manage anemic EPO binding to its receptor followed by internalization leading to erythropoietin levels to administration of HIF stabilizers (Roxadustat, states caused by chemotherapy, bleeding, bone marrow’s malfunctions. acceleration of cell proliferation and differentiation, and inhibition of Desidustat, Daprodustat and Molidustat) were described by the model. To predict the effect of pharmacological intervention on hematopoiesis- apoptosis. PK/PD parameters were calibrated against in vivo data for related clinical endpoints we propose the QSP model of erythropoiesis. single dosage regime of EPO (Fig. 2 and 3). Pharmacokinetics of Dustats MODEL: STRUCTURE Pharmacokinetics of Erythropoietin 800 Daprodustat dose: Desidustat dose: 400 Molidustat dose: 7000 Roxadustat dose: ODE model of erythropoiesis was constructed to comprehensively 10, 25 and 50 mg 2000 25 and 50 mg 25 and 50 mg 100 mg PMID: 26643993 PMID: 28508936 PMID: 29575006 6000 PMID: 27352308 describe cell dynamics from hematopoietic stem cell to circulating RBC. 600 300 1500 5000 400 EPO dose: 300 IU/kg EPO dose: 600 IU/kg EPO dose: 1200 IU/kg 1000 The model includes variables corresponding to specific stages of cell 2000 4000 400 1000 200 300 800 3000 development distinguished based on morphology and surface markers xadustat, ng/mL , IU/L , IU/L , IU/L 1500 o 600 2000 expression. Model processes are cell self-renewal, differentiation, 200 200 500 100 1000 400 1000 plasma Molidustat,ng/mL plasma Desidustat,ng/mL proliferation, migration from bone marrow into circulation and cell plasma R 100 500 plasma Daprodustat,ng/mL 0 0 0 0 200 plasma EPO plasma EPO death. Binding of erythropoietin (EPO) and stem cell factor (SCF) to plasma EPO 0 5 10 15 20 0 20 40 60 0 5 10 15 20 0 20 40 60 0 0 0 Hours Hours Hours Hours cell-surface receptors regulates cell dynamics with feedback on the 0 50 100 150 200 0 50 100 150 200 0 50 100 150 200 receptor expression modulated by interleukine-3 (IL-3). Hypoxia- Hours Hours Hours Inducible Factor (HIF) stabilizers (Roxadustat, Desidustat, Daprodustat Figure 5: Pharmacokinetics of administered dustats. and Molidustat) included in the model prevent the degradation of HIF, Figure 2: Model calibration: Pharmacokinetics of subcutaneously administered erythropoietin. Lines - simulation, dots - data adapted from PMIDs: 9797798, 15317827. thereby inducing synthesis of EPO mRNA. Upregulation of EPO contributes to a negative feedback on HIF degradation through Pharmacodynamics of Dustats increased hemoglobin production (Fig. 1). The model was calibrated across published in vitro/in vivo data including cell expansion under Pharmacodynamics of Erythropoietin 40 160 Daprodustat dose: 7 Desidustat dose: Molidustat dose: Roxadustat dose: growth factors and cytokines exposure in vitro, flow cytometry cell 700 140 10, 25 and 50 mg 6 25 and 50 mg 35 25 and 50 mg 100 mg 600 , IU/L PMID: 26643993 PMID: 28508936 PMID: 29575006 , IU/L PMID: 27352308 counting of bone marrow aspirates and clinical data of ESAs’ 120 3.5 5 30 3 EPO dose: 300 IU/kg 2.5 EPO dose: 600 IU/kg EPO dose: 1200 IU/kg 500 et et et 100 , IU/L , IU/L 4 administration such as epoetins and HIF stabilizers. The QSP model 3 25 400 2.5 80 2 3 2.5 was implemented in Heta language. 20 300 60 2 2 2 1.5 200 15 40 1 ed plasmaR ed plasmaR ed plasmaR plasma EPO 1.5 plasma EPO 1.5 100 20 0 10 1 1 corrected plasmaEPO 1 0 corrected plasmaEPO 0 −1 5 normaliz normaliz normaliz 0 20 40 60 80 0 20 40 60 80 0 20 40 60 80 0 20 40 60 80 0.5 0.5 0.5 0 200 400 600 800 1000 0 200 400 600 800 1000 0 200 400 600 800 1000 Hours Hours Hours Hours Hours Hours Hours Figure 6: Pharmacodynamics of administered dustats. Figure 3: Model calibration: Pharmacodynamics of subcutaneously administered erythropoietin. Lines - simulation, dots - data adapted from PMIDs: 9797798, 15317827. RESULTS: Parameters Variability VALIDATION: Whole Blood Donation Four different methods to generate virtual patient populations basing The model was validated on the data for erythropoiesis recovery after on experimentally measured mean data and statistics are presented in whole blood donation. poster ID WED-027. These techniques were applied to determine distribution of selected parameters of the QSP model of erythropoiesis. 140 0.5 PMID: 28452395 2 120 5 PMID: 27873242 CONCLUSION 0.4 0 PMID: 27587880 100 , % 0.3 −2 0 80 −4 The proposed comprehensive human erythropoiesis 60 0.2 −6 −5 40 0.1 QSP model describes clinical data and could be seen −8 normalized HB,% 20 normalized Ery 0 as predictive tool for investigation of potential normalized plasmaRet −10 −10 normalized plasmaEPO,% 0 −0.1 pharmacological interventions including epoetins −12 0 2000 4000 6000 0 2000 4000 0 2000 4000 6000 0 2000 4000 6000 Hours Hours Hours Hours and HIF stabilizers, and explanation of observed phenomena. The model is regarded as a branch of developing a general platform of human Figure 4: Prediction of recovery of blood erythropoietin, reticulocytes, erythrocytes and hemoglobin levels Figure 1: General scheme of the erythropoiesis model. after whole blood donation. hematopoiesis..