Structure, chemistry, and pharmacokinetics of intravenous iron agents.

Structure and Chemistry All intravenous (IV) iron agents are colloids that consist of spheroidal iron-carbohydrate nanoparticles. At the core of each particle is an iron-oxyhydroxide gel. The core is surrounded by a shell of carbohydrate that stabilizes the iron-oxyhydroxide, slows the release of bioactive iron, and maintains the resulting particles in colloidal suspension. IV iron agents share the same core chemistry but differ from each other by the size of the core and the identity and the density of the surrounding carbohydrate. Differences in core size and carbohydrate chemistry determine pharmacologic and biologic differences, including clearance rate after injection, iron release rate in vitro, early evidence of iron bioactivity in vivo, and maximum tolerated dose and rate of infusion. Early experience demonstrated the hazards posed by administering inorganic ferric (Fe ) iron unprotected by carbohydrate. Profound toxicity limited parenteral free ferric iron administration to 8 mg (1), the approximate total iron-binding capacity of transferrin in the plasma of an adult. Formulations that present ferric iron as colloidal ferric hydroxide permitted higher doses, but common and severe hypotensive reactions precluded routine use (2). Chelating the colloidal ferric hydroxide particles with a carbohydrate proved a major advance in improving parenteral iron safety. Investigators who prepared their own saccharated ferric hydroxide administered as much as 1000 mg of iron intravenously over 15 min. Adverse reactions occurred but apparently were not severe because they responded to only “an electric blanket and a fluid ounce of brandy” (3). These reports led to the first commercially available iron-carbohydrate compounds, including iron dextrin (4), saccharated iron oxide (Proferrin; Sharp & Dohme, Inc., Philadelphia, PA) (5), iron dextran (6,7), iron sucrose (8), and ferric gluconate (9,10). IV iron agents that currently are available in North America include only iron sucrose, ferric gluconate, and two iron dextran formulations. We focus discussion here primarily on agents in these three classes. However, multiple other parenteral iron-carbohydrate compounds for IV and intramuscular administration have been produced over the past 50 yr. Most are not currently marketed. Some of these agents differ by trade name but share identical chemistry, whereas others share the same generic name but differ chemically. Compounding the potential for confusion, published reports may reference either trade name or generic class but not both. Thus, to assist interpretation of the literature and minimize confusion, Table 1 lists IV iron agents by generic class, trade name, and current availability. The table includes packaging information because the older literature frequently cites iron doses by volume administered rather than by milligrams. Use of low molecular weight (LMW) dextran to chelate high molecular weight ferric oxyhydroxide particles produced iron dextran. Iron dextran (Imferon; Fisons Ltd., Loughborough, Leicestershire, UK) was first available in the United States and the United Kingdom for intramuscular administration in 1955 (11) and for IV use in 1971. It was withdrawn from the world market in 1996. Early reports confirmed that iron dextran could be administered in doses as high as 2 to 3 g given intravenously over 4 to 10 min (12). More caution followed closely, when investigators found that patients who received iron dextran infusions were prone, at times fatally so, to anaphylaxis (13,14). Moreover, patients who were given high-dose iron dextran experienced severe reactions related to either total iron dose or rate of iron infusion (15). Two other forms of iron dextran remain available in the United States, one of which was introduced recently in Europe (Table 1). Iron sucrose was first used in 1949 in Europe (8). Iron sucrose has been administered in IV push doses up to 200 mg over 2 to 5 min and in IV infusion doses up to 500 mg over 2 to 4 h. Iron sucrose is available in North America, Europe, and most countries worldwide. To our knowledge, IV administration of ferric gluconate was first reported in 1977 (16,17). Ferric gluconate has been administered 125 mg over 10 min and up to 250 mg over 1 to 4 h. Ferric gluconate is available in the United States and several European countries.