A mechanism-based pharmacokinetic/pharmacodynamic model for iron-regulated hematopoietic stem and progenitor cells commitment towards erythroid and megakaryocyte lineages
Authors: Yan Xiaoyu , Cao Kangna , Fan Xiaoqing 
Published: February 2025

Objectives: Iron deficiency is associated with elevated platelet counts (PLT), through mechanisms that are poorly understood. Through in vitro study, we demonstrated that iron influences erythropoiesis and thrombopoiesis by regulating hematopoietic stem and progenitor cells (HSPCs) commitment towards the two lineages. Specifically, a high concentration of iron drives HSPCs into the erythroid lineage, whereas low iron promotes the megakaryocytic lineage. In this study, we aim to 1) further investigate the effect of iron on erythropoiesis and thrombopoiesis in vivo using rats with iron-deficiency anemia (IDA); 2) develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model to quantify the effect of iron on erythropoiesis and thrombopoiesis. Methods: IDA rats received intravenous injections of ferric carboxymaltose at varying doses (3 mg/kg, 15 mg/kg, and 90 mg/kg) or saline QW for two weeks. Hematological parameters including red blood cell count (RBC), hemoglobin (HGB), and PLT were monitored twice a week for seven weeks. The PK profile of serum iron was described by a two-compartment model. A transit compartment model was applied to describe the effect of iron on erythropoiesis and thrombopoiesis[1]. Results: Corroborating in vitro findings,IDA rats exhibited a continuous decline of RBC counts and elevated PLT count, while iron supplementation led to increased RBC and inverted the escalating trend of PLT. This was achieved by introducing a disease factor (DF) affecting the differentiation of HSPCs into burst-forming unit-erythroid (BFU-E)[2]. IV iron supplement increases RBC and rescues elevated PLT by the stimulatory effect of iron on the differentiation of HSPCs into BFU-E and correction of DF. Moreover, IV iron promoted HGB production by enhancing its synthesis rate. The estimates of the lineage-related parameters TRET, TPLT, RBC0, HBG0, and PLT0 were close to physiologic values [1]. The estimated RBC lifespan in the model is 168.4 h, greatly shorter than that in normal rats. It is reasonable because iron deficiency was reported to reduce the lifespan of RBC[3]. DF was estimated to be 0.8748 in the final model, indicating an 87% decrease in the differentiation rate of HSPCs into erythroid lineage compared to healthy conditions. Iron concentration exceeding the cutoff value of 201.284 μg/dL promotes HSPCs towards BFU-E with Smax and SC50 estimated to be 12.63 and 3.144 μg/dL respectively. The Smax and SC50 for stimulating HGB production were 0.7236 and 16.24 μg/dL, respectively. All parameters were estimated with reasonable precision, having relative standard errors (RSE%) below 38.93%. Conclusion: The effect of iron on erythropoiesis and thrombopoiesis was successfully characterized by a mechanism-based PK/PD model. The model provides valuable mechanistic insights into iron-regulated HSPCs commitment towards erythroid and megakaryocyte lineages and holds translational implications for optimizing iron therapy in anemia management.Citations: 1. Fan X, et al. ACS Pharmacol Transl Sci 2023; 6(12):1884-1897.2. Gao W, et al. J Pharmacokinet Pharmacodyn 2011; 38(1):143-162.3. Nagababu E, et al. Free Radic Res 2008; 42(9):824-829.