Research paper
A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer®), a new intravenous iron preparation and its clinical implications

https://doi.org/10.1016/j.ejpb.2011.03.016Get rights and content

Abstract

The treatment of iron deficiency anemia with polynuclear iron formulations is an established therapy in patients with chronic kidney disease but also in other disease areas like gastroenterology, cardiology, oncology, pre/post operatively and obstetrics’ and gynecology. Parenteral iron formulations represent colloidal systems in the lower nanometer size range which have traditionally been shown to consist of an iron core surrounded by a carbohydrate shell. In this publication, we for the first time describe the novel matrix structure of iron isomaltoside 1000 which differs from the traditional picture of an iron core surrounded by a carbohydrate. Despite some structural similarities between the different iron formulations, the products differ significantly in their physicochemical properties such as particle size, zeta potential, free and labile iron content, and release of iron in serum. This study compares the physiochemical properties of iron isomaltoside 1000 (Monofer®) with the currently available intravenous iron preparations and relates them to their biopharmaceutical properties and their approved clinical applications. The investigated products encompass low molecular weight iron dextran (CosmoFer®), sodium ferric gluconate (Ferrlecit®), iron sucrose (Venofer®), iron carboxymaltose (Ferinject®/Injectafer®), and ferumoxytol (Feraheme®) which are compared to iron isomaltoside 1000 (Monofer®). It is shown that significant and clinically relevant differences exist between sodium ferric gluconate and iron sucrose as labile iron formulations and iron dextran, iron carboxymaltose, ferumoxytol, and iron isomaltoside 1000 as stable polynuclear formulations. The differences exist in terms of their immunogenic potential, safety, and convenience of use, the latter being expressed by the opportunity for high single-dose administration and short infusion times. Monofer is a new parenteral iron product with a very low immunogenic potential and a very low content of labile and free iron. This enables Monofer, as the only IV iron formulation, to be administered as a rapid high dose infusion in doses exceeding 1000 mg without the application of a test dose. This offers considerable dose flexibility, including the possibility of providing full iron repletion in a single infusion (one-dose iron repletion).

Graphical abstract

Transmission electron microscopic image of iron isomaltoside 1000.

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Introduction

Parenteral iron therapy is today widely used for the treatment of iron deficiency anemia. Patients with chronic kidney disease (CKD) also frequently need treatment with parenteral iron preparations in addition to erythropoietin stimulating agents [1]. For renal failure patients on dialysis, the average iron requirements due to blood loss are equivalent to 1–3 g of elemental iron per year [2]. This can easily be accomplished by frequent low dose IV iron administrations, during the regular dialysis sessions.

From initial, generalized use in nephrology parenteral iron therapy has spread in recent years to other disease areas; gastroenterology [3], cardiology [4], [5], oncology [6], pre/post operatively [7], obstetrics’, and gynecology [8]. However, care providers in these segments have less frequent patient contact, resulting in an increased demand for convenient administration of large IV iron doses in one clinical session.

Historically, the first parenteral iron preparations were toxic, being administered as an iron oxyhydroxide complex. This problem was circumvented with the introduction of compounds containing iron in a core surrounded by a carbohydrate shell [9]. The currently marketed parenteral iron preparations are considered equally efficacious but vary in molecular size, pharmacokinetics, and adverse reaction profiles. The intravenous iron agents currently available include high molecular weight iron dextran (Dexferrum®), low molecular weight iron dextran (Cosmofer®, Infed®), sodium ferric gluconate (Ferrlecit®), iron sucrose (Venofer®), iron carboxymaltose (Ferinject®/Injectafer®), and ferumoxytol (Feraheme®). High molecular weight iron dextran has been linked to an increased risk of anaphylaxis and anaphylactoid reactions, and it is not available in Europe [10], [11], [12], [13]. Although this problem is very much reduced with low molecular weight iron dextran [10], [11], [12], [13], there is still a test dose requirement and the infusion of larger doses is hampered by a 4–6 h infusion time. Sodium ferric gluconate and iron sucrose can only be used in moderate iron doses due to the relative weakness of the iron complex [14]. Two new parenteral iron compounds, iron carboxymaltose, and ferumoxytol were recently introduced in the EU and the US markets, respectively. The FDA failed to approve iron carboxymaltose for distribution in the USA due to unexplained hypophosphatemia, an increased number of adverse cardiac events and an imbalance in death rates in the treatment arm compared to the control arm in different RCTs [15].

Although more stable than sodium ferric gluconate and iron sucrose, the administration of iron carboxymaltose and ferumoxytol is still limited to a maximum total dose of 1000 mg and 510 mg, respectively.

The newest IV iron agent Iron isomaltoside 1000 (Monofer®) (e.g., iron oligo isomaltoside (1000) as generic name) is developed and manufactured by Pharmacosmos in Denmark and was introduced in Europe in 2010. The carbohydrate isomaltoside 1000 is a pure linear chemical structure of repeating α1-6 linked glucose units, with an average size of 5.2 glucose units and an average molecular weight of 1000 Da, respectively. It is a nonbranched, nonanaphylactic carbohydrate [16], [17], structurally different from branched polysaccharides used in iron dextran (Cosmofer).

The production method and the short nonionic isomaltoside 1000 allows for the construction of a special matrix-like structure with interchanging iron molecules and linear isomaltoside 1000 oligomers. The resulting matrix contains about 10 iron molecules per one isomaltoside pentamer in a strongly bound structure that enables a controlled and slow release of bioavailable iron to iron-binding proteins with little risk of free iron toxicity [18], [19]. This allows iron isomaltoside 1000 to be administered safely as a rapid high dose intravenous infusion or bolus injection offering considerable dose flexibility, including the possibility of providing full iron repletion in a single infusion, the so-called one-dose iron repletion.

This article introduces and compares physicochemical properties of iron isomaltoside 1000 (Monofer®) with currently marketed iron formulations. In addition, this comparative study of polynuclear iron formulations currently used in the treatment of anemic disorders includes perspectives on the relevance of these properties with respect to safety, efficacy, and convenience of administration.

Section snippets

Materials

Sodium ferric gluconate (Ferrlecit®, 12.5 mg Fe/mL in 3.2 mL ampoules; Sanofi-Aventis, Frankfurt, Germany), iron sucrose (Venofer®, 20 mg Fe/mL in 5 mL ampoules; Vifor, München, Germany), low molecular weight iron dextran (CosmoFer®, 50 mg Fe/mL in 2 mL ampoules; Teva, Mörfelden-Walldorf, Germany), iron isomaltoside 1000 (Monofer®, 100 mg Fe/mL in vials; Pharmacosmos, Holbaek, Denmark), iron carboxymaltose (Ferinject®, 50 mg Fe/mL in 2 mL vials; Vifor, München, Germany), and ferumoxytol (Feraheme®, 30 mg

Gel permeation chromatography

The distributions calculated from the GPC chromatograms of the iron preparations show homogenous distributions with the exception of ferumoxytol and iron carboxymaltose which show additional smaller and larger diameter peaks (Fig. 1). The hydrodynamic diameters dh rise in the order iron sucrose < sodium ferric gluconate < iron isomaltoside 1000 < LMW iron dextran < iron carboxymaltose < ferumoxytol (Table 1). Ferumoxytol was eluted near the exclusion volume, indicating that both its diameter and

Structure

Iron isomaltoside 1000 contains isomaltoside 1000, a pure linear chemical structure of repeating α1-6 linked glucopyranose residues. It is an unbranched, nonanaphylactic carbohydrate with an average size of 5.2 glucose units and an average molecular weight of 1000 Da, respectively, structurally different from the branched dextran polysaccharides present in iron dextran. Low molecular weight dextran has a molecular weight around 5000 and on average one α-1-3 branch point per 32 glucose residues.

Conclusions

The analyzed polynuclear iron formulations are all characterized by a nanosized structure resembling Lepidocrocite, Akaganeite, Ferrihydrite, Magnetite or Maghemite, or mixture of these depending on the product. The homogenicity of the products varied a lot with iron isomaltoside 1000 displaying very well defined spherically shaped particles. With the exception of iron carboxymaltose and ferumoxytol, all parenteral iron preparations followed a monomodal size distribution.

13C NMR and molecular

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