Kangna CAO1, Xiaoqing FAN1, Xiaoyu YAN1
1School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong
Introduction: Iron deficiency anemia (IDA) is a serious global public health problem, which affects around 1.6 billion (24.8%) people worldwide, including individuals with chronic kidney disease, inflammatory bowel disease and heart failure[1]. Intravenous (IV) iron therapy, such as ferric carboxymaltose (FCM) has become a cornerstone therapy for IDA treatment, especially for those who cannot tolerate or fail to respond to oral iron supplementation[2]. However, its use is hindered by the limited understanding of tissue iron distribution following therapy and the lack of practical clinical methods to assess tissue iron content[3]. This study aimed to characterize the tissue distribution of iron following FCM administration and predict tissue iron content in both rats and humans using a physiologically-based pharmacokinetic (PBPK) model. Methods: Using an IDA model in rats, we evaluated the tissue-specific distribution of iron and dynamic changes in serum iron biomarkers over time following FCM administration. Rats in the treatment group received a single intravenous dose of 15 mg/kg Ferric carboxymaltose via the tail vein, while those in the IDA control group were given saline. Three rats were sacrificed at 0 hour, 1 hour, 6 hours, 24 hours, 1 week, 3 weeks, and 5 weeks post-treatment to collect samples for tissue iron analysis with ICP-MS and serum iron biomarkers measurement. We developed a PBPK model to characterize tissue iron kinetics. Serum ferritin dynamics was also included in the model to reflect its interplay with iron storage in the body. The model was then scaled to humans using physiological parameters specific to humans[4]. Due to the invasive nature of tissue biopsies, it is challenging to obtain tissue iron data directly in clinical settings. Magnetic resonance imaging (MRI) has provided a non-invasive method to measure tissue iron levels. The MRI-derived relaxation time parameters (T2*/T2/T1) are inversely correlated with tissue iron levels. Previous studies have demonstrated a strong correlation between relaxation time T2/T2* and liver iron concentrations measured via biopsy in patients with hereditary hemochromatosis and transfusion-dependent thalassemia[5, 6]. One study reported MRI data at multiple time points for liver, spleen, and heart following a single dose of FCM in IDA patients[7]. Using this dataset, we simulated tissue iron content with our PBPK model and performed a correlation analysis between the model-predicted tissue iron levels and MRI-derived parameters to validate the model’s ability to predict tissue iron content in humans. Results: The proposed PBPK model accurately captured tissue-specific iron distribution and serum ferritin dynamics in rats, with fold error values all within threefold. Among the analyzed tissues, the bone marrow exhibited the highest partition coefficient (KPBM=110), reflecting the prioritization of iron delivery to support red blood cell production under iron-deficient conditions. Similarly, the liver and spleen, as primary iron storage organs, demonstrated high partition coefficients (KPt) of 22.1 and 29.1, respectively. Notably, the heart displayed a relatively high KPt value of 18.5 among toxicologically relevant tissues (kidney, liver, lung, and heart), suggesting that the heart may have a limited capacity to clear excess iron. This finding raises concerns about the potential risk of cardiac toxicity associated with long-term iron injections and iron overload. Most model parameters were estimated with good precision. However, the permeability-surface area product for the kidney (PSkid) showed relatively high imprecision (RSE = 69.1%), likely due to the marginal iron accumulation observed in the kidney and the greater variability in the experimental data for this tissue. Correlation analysis revealed that model-predicted iron concentrations in the human liver and spleen were strong correlated with MRI-derived T2*, T2, and T1 values (P < 0.001), underscoring the model's ability to predict tissue iron distribution in humans. Conclusion: This study provides critical insights into the tissue distribution of iron following FCM therapy and highlights the clinical potential of utilizing a PBPK approach to predict tissue iron content, optimize dosing strategies, and ultimately enhance the safety and efficacy of iron therapy in clinical practice. References: [1] S.B. Kumar, S.R. Arnipalli, P. Mehta, S. Carrau, O. Ziouzenkova, Iron Deficiency Anemia: Efficacy and Limitations of Nutritional and Comprehensive Mitigation Strategies, Nutrients 14(14) (2022). [2] G. Rostoker, N.D. Vaziri, S. Fishbane, Iatrogenic Iron Overload in Dialysis Patients at the Beginning of the 21st Century, Drugs 76(7) (2016) 741-57. [3] J.L. Babitt, M.F. Eisenga, V.H. Haase, A.V. Kshirsagar, A. Levin, F. Locatelli, J. Malyszko, D.W. Swinkels, D.C. Tarng, M. Cheung, M. Jadoul, W.C. Winkelmayer, T.B. Drüeke, Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference, Kidney Int 99(6) (2021) 1280-1295. [4] D.K. Shah, A.M. Betts, Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human, J Pharmacokinet Pharmacodyn 39(1) (2012) 67-86. [5] J.C. Wood, C. Enriquez, N. Ghugre, J.M. Tyzka, S. Carson, M.D. Nelson, T.D. Coates, MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients, Blood 106(4) (2005) 1460-1465. [6] T.G. St. Pierre, P.R. Clark, W. Chua-anusorn, A.J. Fleming, G.P. Jeffrey, J.K. Olynyk, P. Pootrakul, E. Robins, R. Lindeman, Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance, Blood 105(2) (2005) 855-861. [7] M. Vera-Aviles, S.N. Kabir, A. Shah, P. Polzella, D.Y. Lim, P. Buckley, C. Ball, D. Swinkels, H. Matlung, C. Blans, P. Holdship, J. Nugent, E. Anderson, M. Desborough, S. Piechnik, V. Ferreira, S. Lakhal-Littleton, Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway, Eur Heart J 45(42) (2024) 4497-4508.
Reference: PAGE 33 (2025) Abstr 11361 [www.page-meeting.org/?abstract=11361]
Poster: Drug/Disease Modelling - Other Topics