Single-Dose Pharmacokinetics of Sodium Ferric Gluconate Complex in Iron-Deficient Subjects

Paul A. Seligman, M.D.; Naomi V. Dahl, Pharm.D.; Jur Strobos, M.D., J.D.; Hui C. Kimko, Ph.D.; Rhoda B. Schleicher M.S.; Michael Jones, Ph.D.; Murray P. Ducharme, Pharm.D.

Disclosures

Pharmacotherapy. 2004;24(5) 

In This Article

Abstract and Introduction

Study Objectives: To determine the single-dose pharmacokinetics of intravenous sodium ferric gluconate complex in sucrose injection (SFGC) in iron-deficient human volunteers, and to assess iron transport.
Design: Open-label, randomized study.
Setting: Clinical research facility.
Subjects: Fourteen iron-deficient men and women.
Interventions: Subjects were randomized to receive a single intravenous dose of either SFGC 62.5 mg administered over 30 minutes or SFGC 125 mg over 60 minutes. Five days later, the same subjects were rerandomized to receive a second intravenous dose of SFGC, either 62.5 mg administered over 4 minutes or 125 mg over 7 minutes.
Measurements and Main Results: Blood samples were collected at predefined times before, during, and up to 72 hours after the infusion to determine the single-dose pharmacokinetics of SFGC. Assays were performed for both total iron and transferrin-bound iron, from which drug-bound iron could be calculated. Urine was collected over 24 hours before dosing and for 24 hours after the start of infusion to determine the renal elimination of iron. Clearance of SFGC from serum was rapid and far exceeded rates reported for iron dextran. Pharmacokinetic parameters were unaffected by dose or infusion rate. Serum iron derived from SFGC did not exceed the binding capacity of transferrin. Serum iron from SFGC became rapidly available (< 24 hrs) as transferrin-bound iron, but only after passage through another compartment, presumably the reticuloendothelial system (RES). At least 80% of the administered iron was transported to bone marrow within 24 hours after infusion.
Conclusions: Iron derived from SFGC appears to be rapidly transferred to a bioavailable iron compartment as transferrin-bound iron after digestion in the RES. At the doses administered in this study, liberation of potentially toxic, free iron was not detectable.

Sodium ferric gluconate complex in sucrose injection (SFGC) is an iron formulation marketed in the United States as Ferrlecit (Watson Pharma, Inc., Morristown, NJ). This formulation was approved by the U.S. Food and Drug Administration (FDA) in 1999 for treatment of iron-deficiency anemia in patients undergoing chronic hemodialysis who receive supplemental erythropoietin therapy. Patients who undergo hemodialysis have chronic iron losses and a deficiency of erythropoietin.[1,2] When exogenous erythropoietin is administered, oral iron supplements cannot always supply iron at a rate sufficient to support optimal erythro-poiesis, and intravenous iron is needed.[1,3,4] Before SFGC gained FDA approval, two commercial forms of iron dextran were the only intravenous iron products approved for use in the United States.

The SFGC formulation is effective in treating iron deficiency, and it has a better safety profile than iron dextran, which is associated with rare but potentially serious anaphylactic reactions.[5,6,7] The SFGC is a stable macromolecular complex with an apparent molecular weight of 350,000 ± 23,000 daltons.[8] It is negatively charged at alkaline pH and is present in solution with sodium cations. It is free of ferrous iron and dextran polysaccharides.[8]

In 1959, SFGC was introduced into clinical practice in Germany, where it has been in use ever since. It also has gained acceptance in other European countries. The regulatory environment of that time did not require pharmacokinetic studies before marketing. Dosing recommendations evolved from clinical experience and reports of side effects. German labeling and usage practices over the last 25 years advise administration of 62.5 mg of undiluted SFGC "slowly" or, after dilution in saline, over no less than 20 minutes (3 mg/min). "Slowly" has been interpreted in clinical use as 5-10 minutes (or 6-12.5 mg/min).[5]

The lack of formal pharmacokinetic studies of SFGC may have led to more conservative dosing practices than are warranted. In the United States, the first approved dosage regimen for repletion of iron deficiency in patients undergoing hemodialysis, based on pivotal clinical trials, was SFGC 125 mg diluted in 100 ml normal saline and delivered over 1 hour. Based in part on the results of this study, the package insert, in accordance with FDA specifications, allows 125 mg of undiluted SFGC to be administered without a test dose as a slow intravenous injection, at a rate of up to 12.5 mg/minute.[8] There have been reports of injection at faster rates, but these rates have not been thoroughly studied.[9] In addition, several recent reports have asserted that infusions of 250 mg over 1 hour may be safe.[10,11,12]

The pharmacokinetic properties of iron dextrans are well known.[13] Iron is bound tightly within a dextran complex. These complexes are very stable in circulation. They incorporate slowly into the reticuloendothelial system (RES), where they undergo gradual intracellular degradation leading to release of iron from the RES to transferrin.

A preliminary study with SFGC in one patient undergoing hemodialysis suggested that the half-life of SFGC may be 3-5 hours. It has been hypothesized that such rapid release of iron, although desirable during enhanced erythropoiesis, could have the potential to overwhelm the transport system for iron (called transferrin "oversaturation"[14]), possibly resulting in the release of free iron into the circulation and the development of iron toxicity.

The primary objective of our study was to determine the classic pharmacokinetic parameters (elimination half-life [t1/2], volume of distribution (Vd), and area under the concentration-time curve [AUC]) for SFGC at two infusion rates: 2.1 mg/minute and 16-18 mg/minute. A secondary objective was to measure changes in iron transport and storage parameters (percent transferrin saturation and serum ferritin) during the first 72 hours after SFGC administration.

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