Evaluating Plasma Pharmacokinetics of Intravenous Iron Formulations: Judging Books by Their Covers?

Intravenous (IV) iron formulations provide a clinical treatment option for patients when iron supplementation is required but oral administration is unsuitable because of intolerance or lack of efficacy. IV iron use is increasing worldwide, especially in the chronic kidney disease (CKD) population [1]. Pharmacokinetic (PK) analysis of IV iron formulations is challenging unless the compound can be directly measured or it is manufactured with a radiolabelled form of iron (e.g. Fe) to distinguish the IV iron formulation from endogenous serum iron [2]. It is also not well appreciated by clinicians that IV iron formulations exhibit zero-order or capacity-limited metabolism by the reticuloendothelial system [3]. This results in longer residence time in plasma with higher administered doses, especially with larger molecular weight formulations [3]. Commercially available IV iron formulations consist of an iron oxyhydroxide core surrounded by carbohydrate shells of various sizes and polysaccharide branch characteristics in colloidal suspensions [4]. The size of commercially available IV iron–carbohydrate complexes range from 5 to 100 nm and thus meet the definition for nanoparticles, enhancing the complexity of PK studies of these agents [4]. In this issue of Clinical Pharmacokinetics, MuellerPlock et al. [5] evaluate plasma ferumoxytol data from healthy subjects and CKD patients, using a population PK approach seeking to bridge the PK profiles between populations with iron deficiency anaemia. This is arguably one of the larger PK analyses of IV iron plasma data to date, and ferumoxytol offers the distinct advantage of being able to be directly measured by nuclear magnetic resonance. The authors show that, as previously published, ferumoxytol plasma concentration–time profiles were best fitted with a two-compartment model with nonlinear elimination, consistent with the known capacity-limited metabolism by the reticuloendothelial system [3]. A limitation of Mueller-Plock et al.’s analysis, as well as the collective published data on IV iron plasma PK, is that these data likely represent an oversimplification of the PK profile of IV iron–carbohydrate complexes. Ferumoxytol is a superparamagnetic iron oxide nanoparticle (SPION), which was originally developed for use in magnetic resonance imaging (MRI). Biodistribution data for SPIONs demonstrate that different carbohydrate shell structures determine the relative uptake by endothelial and lymphatic cells, as well as by the reticuloendothelial system [6]. Thus, analysis of only short-term plasma PK provides limited information on the ultimate disposition and fate of these agents. Ultimately, the complexity of IV iron–carbohydrate nanoparticle formulations has important implications with regard to both efficacy and safety in treatment of iron deficiency anaemia. These agents have not been well studied with regard to comparative biodistribution, metabolic fate, and potential extracellular and intracellular deposition profiles, and further evaluation of these agents is urgently needed. Analysing short-term plasma data to infer IV iron–carbohydrate PK profiles has been typically acceptable for IV iron registry trials; however, on the basis of the SPION data in the MRI literature, these agents exhibit complicated PK and pharmacodynamic (PD) profiles, which can differ vastly between agents because of carbohydrate shell heterogeneity [6]. Thus, although shortterm plasma PK profiles among groups of healthy and This comment refers to the article available at doi:10.1007/s40262-014-0203-9.