A whole-body mechanistic physiologically-based pharmacokinetic modeling of intravenous iron

Abstract

AbstractIron is essential for every cell of the mammalian organism. Iron deficiency is a major public health issue worldwide. Intravenous (IV) iron therapy has been used to treat anemia. 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. Patients are known to suffer adverse effects from excessive iron accumulation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model of iron in mice and validate its application for predicting iron disposition in rats and humans. Previously published data on iron were collected for constructing the PBPK model of iron in mice, and then extrapolated to rats and humans based on physiologically and chemically specific parameters relevant to each species. The PBPK model characterized the distribution of iron in mice successfully. The model based on extrapolation to rats accurately simulated the ferric carboxymaltose (FCM) PK profiles in rat tissues. Similarly, the observed and simulated serum PK of FCM in humans were in reasonable agreement. This mechanistic whole-body PBPK model is useful for understanding and predicting iron effects on different species. It also establishes a foundation for future research that incorporates iron kinetics and biodistribution, along with related clinical experiments. This approach could lead to the development of effective and personalized iron deficiency anemia treatments. Graphical Abstract Major components and processes of whole-body systemic iron trafficking.