Advertisement

International Journal of Hematology

, Volume 107, Issue 5, pp 519–527 | Cite as

Pharmacokinetics, pharmacodynamics, safety, and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in Japanese volunteers with iron-deficiency anemia

  • Katsuya Ikuta
  • Asami Shimura
  • Masaru Terauchi
  • Kazuyoshi Yoshii
  • Yoshihiro Kawabata
Original Article

Abstract

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.

Keywords

PK/PD Ferric carboxymaltose Japanese Iron deficiency anemia (IDA) 

Notes

Acknowledgements

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

12185_2018_2400_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 17 kb)
12185_2018_2400_MOESM2_ESM.jpeg (105 kb)
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

References

  1. 1.
    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
  2. 2.
    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
  3. 3.
    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
  4. 4.
    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
  5. 5.
    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
  6. 6.
    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
  7. 7.
    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
  8. 8.
    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
  9. 9.
    Danielson BG. The structure, chemistry, and pharmacokinetics of intravenous iron agents preparations. J Am Soc Nephrol. 2004;15:S93–8.PubMedGoogle Scholar
  10. 10.
    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
  11. 11.
    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
  12. 12.
    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
  13. 13.
    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

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Katsuya Ikuta
    • 1
  • Asami Shimura
    • 2
  • Masaru Terauchi
    • 2
  • Kazuyoshi Yoshii
    • 3
  • Yoshihiro Kawabata
    • 3
  1. 1.Division of Gastroenterology and Hematology/Oncology, Department of MedicineAsahikawa Medical UniversityAsahikawaJapan
  2. 2.Clinical Research 2Zeria Pharmaceutical Co., Ltd.TokyoJapan
  3. 3.Central Research LaboratoriesZeria Pharmaceutical Co., Ltd.KumagayaJapan

Personalised recommendations