A Whole-body Mechanistic Physiologically-based Pharmacokinetic Modeling of Intravenous Iron
Authors: Yan Xiaoyu , Fan Xiaoqing , Cao Kangna , Wong Raymond 
Published: February 2025

Objectives: Intravenous (IV) iron therapy has been used to treat iron deficiency anemia (IDA), but its quantitative relationship between the pharmacokinetics and biodistribution remains unclear. Understanding the iron disposition in tissues is crucial for optimizing IV iron dosage in anemia management [1]. Here, we aim to develop a whole-body mechanistic physiologically-based pharmacokinetic (PBPK) model to investigate the iron-distribution in mice, and extrapolate to rats and humans to examine the utility of the model for predicting the tissue disposition of iron across species.Methods: The PK study of iron in mice concerning iron disposition in multiple tissues under different iron statuses was used to develop the PBPK model[2]. The model included thirteen organs, namely heart, liver, spleen, lung, kidney, brain, bone, muscle, fat, skin, gut, red blood cells (RBCs), and plasma. Iron concentrations in other organs were not determined and included in the “remainder” compartment. The model was extrapolated to rats and humans by taking into account the interspecies differences in physiological parameters[3-4]. Since ferric carboxymaltose (FCM) is an iron-carbohydrate complex preparation, the model was modified slightly to mimic the direct and indirect iron release[5]. Modeling input physiological parameters required in developing the PBPK model in mice, rats, and humans with cardiac output, organ volume, and blood flow rate were obtained from papers[6-8]. The organ to plasma partition coefficient for the same type of tissues and the iron daily loss rate values were assumed to be identical among species. The production rate of RBCs were scaled from rats to humans using an allometric equation based on the lifespan of RBCs. The model was implemented in NONMEM 7.5.1 where the ordinary differential equations were solved by ADVAN15 subroutine, and the FOCEI algorithm was used for parameter estimation.Results: The proposed PBPK model was able to capture the iron concentration-time profiles in plasma and tissues. High values were estimated in IDA mice (0.3175 nmol/L/h) compared with the normal (0.2175 nmol/L/h) and iron-loaded mice (0.03881 nmol/L/h), indicating that iron was consumed for the production of RBCs during IDA, consistently with the high tissue concentrations of iron measured in iron-loaded mice. The scaled model simulations acceptably approximated the observed time-concentration profiles in rats with IDA received a single IV dose of 30 mg Fe/kg of FCM. The final model demonstrated an acceptable prediction of the serum concentration-time profile of iron in patients with IDA following IV dose regimens of FCM.Conclusions: A PBPK model was developed, which is capable of describing the iron concentration-time profiles in serum and various tissues after receiving pure iron and FCM, as evidenced by reproducing the observed PK data. The model may have clinical applications in the efficacy and safety assessment of iron therapy.Citations: [1] O.M. Gutiérrez, Treatment of Iron Deficiency Anemia in CKD and End-Stage Kidney Disease, Kidney Int Rep 6(9) (2021) 2261-2269.[2] K. Schümann, B. Szegner, B. Kohler, M.W. Pfaffl, T. Ettle, A method to assess 59Fe in residual tissue blood content in mice and its use to correct 59Fe-distribution kinetics accordingly, Toxicology 241(1-2) (2007) 19-32.[3] F. Funk, K. Weber, N. Nyffenegger, J.A. Fuchs, A. Barton, Tissue biodistribution of intravenous iron-carbohydrate nanomedicines differs between preparations with varying physicochemical characteristics in an anemic rat model, Eur J Pharm Biopharm 174 (2022) 56-76.[4] P. Geisser, J. Banké-Bochita, Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia, Arzneimittelforschung 60(6a) (2010) 362-72.[5] M.W. Garbowski, S. Bansal, J.B. Porter, C. Mori, S. Burckhardt, R.C. Hider, Intravenous iron preparations transiently generate non-transferrin-bound iron from two proposed pathways, Haematologica 106(11) (2021) 2885-2896.[6] B. Davies, T. Morris, Physiological parameters in laboratory animals and humans, Pharm Res 10(7) (1993) 1093-5.[7] R.P. Brown, M.D. Delp, S.L. Lindstedt, L.R. Rhomberg, R.P. Beliles, Physiological parameter values for physiologically based pharmacokinetic models, Toxicol Ind Health 13(4) (1997) 407-84.[8] C. Hall, E. Lueshen, A. Mošat, A.A. Linninger, Interspecies scaling in pharmacokinetics: a novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo, J Pharm Sci 101(3) (2012) 1221-41.