Iron-deficiency anemia (IDA) is the most common form of anemia. Iron replacement therapy is an effective treatment, but oral and previously available intravenous (IV) formulations in Japan have disadvantages such as side effects, immunogenic reactions, low dose per tablet/vial, and the need for continuous administration. Ferric carboxymaltose (FCM), which overcomes these limitations, is widely used as an IV iron preparation outside of Japan. In this single-center, open-label, single-dose escalation study, we investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of FCM in Japanese subjects. Twenty-four Japanese IDA patients, diagnosed by hemoglobin, serum ferritin, and transferrin saturation, were assigned in equal groups to the 100, 500, 800, and 1000 mg iron dose arms. All subjects completed the study without important protocol deviations. Mean total serum iron concentrations showed a rapid, dose-dependent increase after FCM injection, reaching a maximum within 1 h. Mean reticulocyte counts significantly increased in all arms, suggesting improved hematopoietic function. Fourteen of 24 subjects experienced adverse events, but these were neither serious nor led to drug interruption. The PK/PD and safety profiles were similar in Japanese and European subjects. Ferric carboxymaltose is safe for administration in Japanese patients with IDA.
PK/PD Ferric carboxymaltose Japanese Iron deficiency anemia (IDA)
This is a preview of subscription content, log in to check access
The authors are grateful to the patients and their families for their contributions. We would like to thank A. Urae for collaboration on this work.
Compliance with ethical standards
Conflict of interest
The present study was performed as phase Ib study funded by Zeria Pharmaceutical Co., Ltd. Katsuya Ikuta is involved in this study as a medical expert. Asami Shimura, Masaru Terauchi, Kazuyoshi Yoshii and Yoshihiro Kawabata are an employees of Zeria Pharmaceutical Co., Ltd.
Supplementary material 2 (JPEG 105 kb) Supplemental Fig. 1 Line chart of the mean TSAT between 1 day prior to FCM administration and 168 h after administration. Mean TSAT was increased rapidly after administration and reached almost 100% at 500, 800 and 1000 mg iron dose arms. At 100 mg iron dose arm, mean TSAT increased once up to 42.55% immediately after administration, and continued to increase gradually to reach a maximum at 24 h. ●: 100 mg iron, ○: 500 mg iron, △: 800 mg iron, ◊: 1000 mg iron
World Health Organization. Iron deficiency anemia—assessment, prevention, and control. A guide for program managers. 2001. Report No.: Document WHO/NHD/01.3.Google Scholar
Adamson JW. Iron deficiency and other hypoproliferative anemias. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, editors. Harrison’s principles of internal medicine. 18th ed. New York: McGraw-Hill Companies; 2013. p. 844–51.Google Scholar
Neiser S, Wilhelm M, Schwarz K, Funk F, Geisser P, Burckhardt S. Assessment of dextran antigenicity of intravenous iron products by an immunodiffusion assay. Prot Nephrol Hypert. 2011;25:219–24.Google Scholar
Neiser S, Koskenkorva TS, Schwarz K, Wilhelm M, Burckhardt S. Assessment of dextran antigenicity of intravenous iron preparations with enzyme-linked immunosorbent assay (ELISA). Int J Mol Sci. 2016;17:1185–94.CrossRefPubMedCentralGoogle Scholar
Girelli D, Ugolini S, Busti F, Marchi G, Castagna A. Modern iron replacement therapy: clinical and pathophysiological insights. Int J Hematol. 2018;107:16–30.CrossRefPubMedGoogle Scholar
Geisser P, Banke-Bochita J. Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia. Arzneimittelforschung. 2010;60:362–7.PubMedGoogle Scholar
Gupta A, Winer K, Econs MJ, Marx SJ, Collins MT. FGF-23 is elevated by chronic hyperphosphatemia. J Clin Endocrinol Metab. 2004;89:4489–92.CrossRefPubMedGoogle Scholar
Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005;90:1519–24.CrossRefPubMedGoogle Scholar
Danielson BG. The structure, chemistry, and pharmacokinetics of intravenous iron agents preparations. J Am Soc Nephrol. 2004;15:S93–8.PubMedGoogle Scholar
Seligman PA, Schleicher RB. Comparison of methods used to measure serum iron in the presence of iron gluconate or iron dextran. Clin Chem. 1999;45:898–901.PubMedGoogle Scholar
Wolf M, Koch TA, Bregman DB. Effect of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;28:1793–803.CrossRefPubMedGoogle Scholar
Schaefer B, Würtinger P, Finkenstedt A, Braithwaite V, Viveiros A, Effenberger M, et al. Choice of high-dose intravenous iron preparation determines hypophosphatemia risk. PLoS One. 2016;11:e0167146.CrossRefPubMedPubMedCentralGoogle Scholar
Bager P, Hvas CL, Dahlerup JF. Drug-specific hypophosphatemia and hypersensitivity reactions following different intravenous iron infusions. Br J Clin Pharmacol. 2017;83:1118–25.CrossRefPubMedGoogle Scholar