Kangna Cao (1), Xiaoqing Fan (1), Xiaoyu Yan (1), *
(1) School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China SAR.
Introduction: Iron is an essential element for almost all living organisms. Iron deficiency causes anemia, which is associated with reduced hemoglobin (HGB) and red blood cell counts (RBC). Paradoxically, iron deficiency is also associated with elevated platelet counts, through mechanisms that are not well understood. Notably, platelets are derived from megakaryocytes, which share the common progenitor stem cells, megakaryocytic-erythroid progenitors (MEPs), with erythrocytes. Therefore, we hypothesize that systemic iron availability regulates hematopoietic stem and progenitor cells (HSPCs) commitment toward erythroid and megakaryocyte lineages. Through our in vitro study, it has been demonstrated that a high concentration of iron drives HSPCs into the erythroid lineage and inhibits differentiation into the megakaryocyte lineage, whereas a low concentration of iron promotes the differentiation of HSPCs into the megakaryocyte lineage and limits differentiation into the erythroid lineage.
Objectives: The current study aims to 1) further investigate the effect of iron on erythropoiesis and thrombopoiesis in an in vivo study using rats with iron-deficiency anemia (IDA); 2) develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model to quantify the effect of iron on HSPCs differentiation towards erythroid and megakaryocyte lineages.
Methods: Iron deficiency anemia in Sprague-Dawley rats was induced by maintaining an iron deficiency diet during the whole course of the experiment and phlebotomizing twice a week for the first three weeks1,2. IDA rats subsequently received intravenous (IV) injections of ferric carboxymaltose at varying doses (3 mg/kg, 15 mg/kg, and 90 mg/kg) or saline once weekly for two weeks. Hematological parameters including red RBC, HGB, and platelet count (PLT) were monitored twice a week until seven weeks after the first dosing. The pharmacokinetic profile of serum iron was described by a two-compartment model with linear elimination. A transit compart model based on ordinary differential equations was applied to describe the effect of iron on erythropoiesis and thrombopoiesis3. The model was implemented in NONMEM 7.5.1 (ICON LLC) with EM algorithm for parameter estimation.
Results: Compared with healthy rats, IDA rats were characterized with significantly decreased HGB, while intravenous iron supplements increased HGB in a dose-dependent manner. With the progression of iron deficiency, 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. In the final mechanism-based PK/PD model, the estimated baseline of RBC, HGB, and PLT were 7.144×1012 cells/L, 9.19 g/dL, and 2.174×1012 cells/L, respectively, which were close to the physiologic values4. The estimated lifespan of RBC and PLT were 168.4 h and 84.76 h, respectively. A disease factor, DF, was added on the differentiation rate of MEPs into burst-forming unit-erythroid (BFU-E), to characterize the continuously declining RBC and elevated PLT in IDA rats5. The estimated value of DF was 0.8817. IV iron supplement would increase RBC and rescue elevated PLT by the stimulatory effect of iron concentration on the differentiation of MEP into BFU-E and correction of DF. Smax for iron supplement to correct DF was fixed to 1, and SC50 was estimated to be 1000 ug/dL. The cutoff value for iron concentration to stimulate MEP into BFU-E was estimated to be 4.284 ug/dL. The Smax and SC50 of this stimulatory effect were 12.27 and 4.119 ug/dL, respectively. All parameters were estimated with reasonable precision with RSE% below 17.42%.
Conclusion: The effect of iron on HSPCs differentiation towards erythroid and megakaryocyte lineages in vivo was successfully characterized by a mechanism-based PK/PD model. We emphasize the importance of not only HGB and RBC but also PLT count as crucial biomarkers in iron therapy. The developed PK-PD model provides valuable mechanistic insights into iron-regulated HSPCs commitment towards erythroid and megakaryocyte lineages and holds promise as a useful tool for dose optimization of IV iron agents in anemia management.
References:
[1] De Souza LV, Hoffmann A, Fischer C, et al. Comparative analysis of oral and intravenous iron therapy in rat models of inflammatory anemia and iron deficiency. Haematologica 2023; 108(1): 135-49.
[2] Theurl I, Aigner E, Theurl M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009; 113(21): 5277-86.
[3] Fan X, Krzyzanski W, Wong RSM, Liu D, Yan X. Novel Combination of Erythropoietin and Romiplostim to Treat Chemotherapy-Induced Anemia and Thrombocytopenia via Pharmacodynamic Interaction on Hematopoietic Stem and Progenitor Cells. ACS Pharmacol Transl Sci 2023; 6(12): 1884-97.
[4] Fan X, Krzyzanski W, Wong RSM, Yan X. Fate Determination Role of Erythropoietin and Romiplostim in the Lineage Commitment of Hematopoietic Progenitors. J Pharmacol Exp Ther 2022; 382(1): 31-43.
[5] Gao W, Bihorel S, DuBois DC, Almon RR, Jusko WJ. Mechanism-based disease progression modeling of type 2 diabetes in Goto-Kakizaki rats. J Pharmacokinet Pharmacodyn 2011; 38(1): 143-62.
Reference: PAGE 32 (2024) Abstr 10795 [www.page-meeting.org/?abstract=10795]
Poster: Drug/Disease Modelling - Other Topics