Progress in intravenous iron treatment

Iron compounds for parenteral use have been available for more than 60 years [1] [2]. For many years the use of intravenous (i.v.) iron formulations was restricted to a limited number of patients with severe iron-deficiency anaemia (IDA) for the following reasons: (1) in IDA, haemoglobin (Hb) regeneration with i.v. iron was equivalent to oral iron [3]; (2) parenteral iron treatment was more expensive; and (3) side-effects, including anaphylactic events, were more serious with i. v. iron than with oral iron [4].

After ten years of clinical experience, the following indications for i.v. iron were mentioned in a state of the art review: (1) intolerance of oral iron due to severe side-effects; (2) serious disorders of the digestive tract, such as inflammatory bowel disease, and the possibility of disease activation; (3) iron malabsorption; (4) severe bleeding disorders of the upper digestive tract when blood loss exceeds the maximum absorption capacity of oral iron [5]. Patients undergoing haemodialysis were not mentioned yet.

In 1975, physicians globally were able to prescribe iron dextran (known as a stable complex, available for i. v. and intramuscular injection) [6]. Data on ferrokinetic parameters and iron distribution in the body were previously known [7]. One advantage of iron dextran was that treatment was possible as a “total dose infusion” [8]. However, very heavy iron deposits were observed in the reticulo-endothelial system (RES), indicating slow mobilization of iron while the Hb concentration remained uncorrected. Anaphylactic, sometimes lethal, events associated with ferric hydroxide dextran were also mentioned [9] [10] [11], and these were attributed to pollution with Fe²⁺; consequently the use of old ampules was not recommended. The second available compound was iron-sorbitol-citrate, a rather small and unstable complex that could only be used for (painful) intramuscular injection [12]. Both drugs are no longer available in most countries.

The use of i. v. iron, and its acceptance as a well-tolerated and reliable treatment, has increased tremendously after the introduction of recombinant human erythropoietin (rhEPO) in patients undergoing dialysis, in whom absorption of oral iron is very poor, while much iron is needed due to enhanced erythropoietic activity [13] [14] [15] [16]. Nephrologists contributed considerably to the present experience in administration of i.v. iron [17]. The number of indications for i. v. iron treatment has expanded into other areas of medicine for which data show that i.v. iron was more effective than oral iron, having an equal or superior safety profile, including chemotherapy-induced anaemia [18] [19], postpartum anaemia [20] [21], abnormal uterine bleeding [22], inflammatory bowel disease [23] [24], chronic heart failure [25] and transplantation [26].

The introduction of second-generation i. v. polynuclear iron(III)-hydroxide carbohydrate complexes, mostly lacking the “feared” immunogenetic properties of the initial iron dextran compounds, has contributed to the improved tolerability and widely accepted use of i. v. iron [27]. In particular, iron sucrose (iron saccharate) is considered to be a well-tolerated drug [28], accepted by physicians and patients despite some disadvantages related to its molecular stability. The stability of iron sucrose is better than that of sodium ferric gluconate but less than that of iron dextran [29]. Plasma iron species were investigated in stable haemodialysis patients treated with rhEPO receiving 100 mg iron as i. v. iron sucrose in 6 min [30]. Blood was collected after 1,10 and 60 min and 2 days later. After 1 minute, total serum iron increased from 11.1 to 219.3 µmol/l (mean values). “Transferrin saturation” (TSAT) increased from 26% to 491% [30]. The very high values for TSAT after i. v. iron injection are, as ignored in most other publications, artefacts due to the fact that TSAT is a calculated value derived from measurement of serum iron (including iron complexes that cannot bind to transferrin) and either latent iron-binding capacity or total serum transferrin. Non-transferrin bound iron (NTBI), detected with high-performance liquid chromatography, increased from 0.90 to 2.90 µmol/l [30]. All differences were significant (p < 0.001), and all parameters returned to baseline after 2 days [30]. It was concluded that NTBI exists in the plasma of patients undergoing dialysis after infusion of iron sucrose ([Fig. 1]). It was also demonstrated that small molecular NTBI existed in the presence of many free-iron binding sites on transferrin as in 6 M urea gel electrophoresis of transferrin; during the observation period no shift could be detected from apotransferrin and monoferric transferrin to diferric transferrin [30]. In another, in vivo, study it was demonstrated that i.v. injection of 100 mg iron as iron sucrose in healthy volunteers induced a greater than four-fold increase in NTBI [31]. A time-controlled study was performed using saline infusion. Vascular ultrasound was used to assess endothe-lium-dependent vasodilation at baseline, and 10 and 240 min after iron sucrose infusion [31]. A transient, significant (p < 0.01) reduction of flow-mediated dilation was observed 10 min after infusion of iron sucrose, when compared with saline in the same individuals. In vivo radical formation was assessed by electron spin resonance. The generation of superoxide in whole blood increased significantly 10 and 240 min after infusion of iron sucrose by 70 and 53%, respectively [31]. It was concluded that iron infusion at the currently used therapeutic dose for i. v. iron supplementation leads to increased oxygen radical stress and acute endothelial dysfunction [31]. Such effects will contribute to the side-effects that occur when larger doses of the drug are injected. A total dose infusion with iron sucrose is not possible [32]. Chronic effects leading to accelerated atherosclerosis, in particular in patients undergoing haemodialysis, may occur [33] [34]. Clinical studies in this matter will probably be inconclusive as to whether the beneficial effects of Hb correction may balance the atherogenic effects of renal disease.

Fig. 1: Nutrient iron, in individuals who do not suffer from iron overload disease, is safely distributed in plasma from iron donor cells (mainly intestinal mucosa and macrophages) to iron acceptor cells, needing iron for proliferation and growth (mainly bone marrow), while excess iron is safely stored in ferritin and haemosiderin (mainly in macrophages and hepato-cytes). During i.v. iron treatment, large and mainly stable iron complexes travel safely to the spleen and liver, where iron is liberated from the iron-sugar complex. Depending on their stability, smaller or larger free iron-sugar complexes can be found in the plasma, unable to donate iron to transferrin and called non-transferrin bound iron (NTBI), which may interact with many cell systems causing oxidative damage.(Adapted from Marx JJM, Hider RC. Iron: an essential but potentially harmful nutrient. Eur J Clin Invest 2002:32 (Suppl 1):1–2. With permission from John Wiley & Sons, Inc.)

The biological effects of NTBI, Fe(II) ammonium sulphate, as well as Fe(III) citrate, were studied in monocytes and human endothelial cells [35] [36] [37]. There was clear evidence for increased firm adhesion of monocytes to endothelial cells, and subsequent transendothelial migration, due to increased concentrations of NTBI in the medium. The effects of NTBI did not occur on the cell surface but were associated with the intracellular formation of oxygen radicals, enhancing the expression of adhesion proteins in both monocytes and endothelial cells. Inhibitions of these effects could be achieved by iron chelators and oxygen radical scavengers. After transendothelial migration, monocytes transform into foam cells, which are crucial for formation of atherosclerotic plaques.

Recently, Vifor (International) Inc., St. Gallen, Switzerland, has introduced a promising, new i. v. iron compound - ferric carboxymaltose (FCM, Ferinject®) - a high molecular weight, stable, dextran-free iron complex [38] [39]. In contrast with the equally stable iron dextran, immunogenicity is rare. In vitro investigations demonstrated that, after i.v. doses of 100 mg iron as FCM, no increase of potentially toxic plasma NTBI was found [40] [41]. In accordance with these characteristics, large dose infusions and push injections are possible, which are more cost effective and patient friendly than frequent i.v. infusions, particularly in predialysis patients [38]. If no increase of NTBI occurs during treatment with FCM, there would still remain a chronically increased NTBI in many patients undergoing haemodialysis compared with normal individuals [41]. The health impact of a chronic, small increase of NTBI, however, is not clear. No increase of cardiovascular pathology was found in a large population of postmenopausal women, compared with those with high and low plasma NTBI values within the normal range [42].

In this issue of Arzneimittel-Forschung/Drug Research some reviews and original articles are brought together regarding chemistry, pharmacology, toxicology, and trans-placental passage of FCM, as well as pharmacokinetics, and efficacy and safety in patients with mild IDA and with gastrointestinal bleeding. The results support the favourable safety profile and convenience of FCM and provide interesting information for clinicians treating patients with IDA.

Much has changed in i. v. iron therapy since its introduction more than 60 years ago. Patients do not have to fear the risk of mortality during treatment for a benign condition such as IDA. Painful intramuscular iron injections are obsolete. Compared with iron sucrose, treatment with FCM is more convenient and cost effective. The atherosclerotic threats due to oxidative effects on monocyte-endothelium interaction or following reperfusion injury, not discussed in this introduction, can most probably be prevented by replacing labile iron with well-tolerated and stable iron polymers.

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