Xiaoqing Fan (1), Kangna Cao (1), Raymond S. M. Wong (2), Xiaoyu Yan (1)
(1) School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China SAR. (2) Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China SAR.
Introduction: Iron is essential for every cell of the mammalian organism. Iron deficiency, with or without anemia, is frequent worldwide, representing a major public health problem. Intravenous (IV) iron therapy has been used to treat anemia in patients associated with chronic kidney disease. However, IV iron therapy is known far away from ideal because the quantitative relationship between the pharmacokinetics and biodistribution of IV iron under different iron statuses remains unclear. The unwanted iron accumulation in patients is known to lead to adverse effects. Optimization of IV iron agent dosage has been identified as a high priority for future research in anemia management [1]. Given the complexity of the PK behavior of IV iron agents, understanding the iron disposition in various tissues (including plasma) post-treatment is crucial for optimizing the dose.
Objectives:
- To develop a whole-body mechanistic physiologically-based pharmacokinetic (PBPK) model to investigate the influence of iron status on body iron-distribution in mice.
- Extrapolation of the mouse PBPK model 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 provided the most informative data concerning iron disposition in multiple tissues under different iron statuses, it was used to develop the mouse PBPK model[2]. The model included thirteen organs, namely heart, liver, spleen, lung, kidney, brain, bone, muscle, fat, skin, gut, red blood cells, and plasma. Iron concentrations in other organs such as the thymus were not determined and therefore included in the “remainder” compartment. The model was extrapolated to rats first and then to humans by taking into account the interspecies differences in physiological parameters (body weight, cardiac output, organ volume, and blood flow), because there are more data in the rat study[3] compared with the human study[4]. Since the third generation IV iron preparation ferric carboxymaltose (FCM) is an iron-carbohydrate complex preparation (IVIP) that is different from pure iron solution, the model was modified slightly to mimic the direct (circulating IVIP-to-plasma) and indirect (IVIP-to-macrophage-to-plasma) 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 published papers[6-8]. The organ to plasma partition coefficient for the same type of tissues and the iron unavoidable daily loss rate values were assumed to be identical among species. The production rate of red blood cells (RBCs) for humans 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 (ICON LLC) 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 various tissues, with model prediction in close agreement with the experimental observed concentration-time profiles. High values were estimated in IDA mice (0.3175 nmol/L/h) compared with the normal mice (0.2175 nmol/L/h) and iron-loaded mice (0.03881 nmol/L/h), while low values were estimated for bone, liver, spleen, heart, and kidney compartments in IDA mice compared with the normal and iron-loaded mice, indicating that iron was consumed for the production of RBCs during IDA situation, 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 translational PBPK model was developed, which is capable of describing the iron concentration-time profiles in serum and various target tissues after receiving pure iron and FCM, as evidenced by reproducing the observed PK data. The model also provides mechanistic insights regarding the mechanism of action of iron, which may have clinical applications in the efficacy and safety assessment of iron therapy.
References:
[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.
Reference: PAGE 32 (2024) Abstr 10791 [www.page-meeting.org/?abstract=10791]
Poster: Drug/Disease Modelling - Absorption & PBPK