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Clinical Pharmacokinetics

, Volume 52, Issue 12, pp 1063–1083 | Cite as

Clinical Pharmacokinetics and Pharmacodynamics of Erythropoiesis-Stimulating Agents

  • Sameer Doshi
  • Wojciech Krzyzanski
  • Susan Yue
  • Steven Elliott
  • Andrew Chow
  • Juan José Pérez-Ruixo
Review Article

Abstract

The cloning of the EPO gene in the early 1980s allowed for the development of recombinant erythropoietins and analogues [erythropoiesis-stimulating agents (ESAs)], offering an alternative to transfusion as a method of raising haemoglobin (Hb) levels, which have been used for more than 20 years to treat anaemia in millions of anaemic patients. There are now a number of ESAs available worldwide for the treatment of anaemia, approved for different routes of administration (intravenous and subcutaneous) and dosing intervals (three times weekly, weekly, biweekly and monthly). In this review, we discuss the pharmacokinetic characteristics, including absorption, distribution and elimination processes, across the different ESAs. Incomplete and slow lymphatic absorption, with limited extravascular distribution, and minor contributions of the target-mediated drug disposition to the overall elimination are the common characteristics across the marketed ESA. Additionally, we assess the similarities and differences of ESAs related to pharmacodynamics in the context of the different biomarkers used to monitor the magnitude and duration of the effect, and introduce the concept of the minimum effective concentration of the ESA. The relationship between the minimum effective concentration and the half-life suggests that the time during which drug concentrations are above the minimum effective concentration is the main determinant of ESA efficacy in increasing Hb levels. The tolerance phenomenon and its physiological mechanism and implications for ESA dosing are discussed. Finally, the areas of future clinical pharmacology research are envisioned.

Keywords

Chronic Kidney Disease Chronic Kidney Disease Patient Darbepoetin Alfa Minimal Effective Concentration TMDD Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Sameer Doshi, Susan Yue, Andrew Chow and Juan José Pérez-Ruixo are employees of Amgen Inc. and owned stock in Amgen Inc. at the time when the review was written. Wojciech Krzyzanski was a consultant for Amgen Inc. and did not receive any consultation fees for contributing to the current review. Steven Elliott is a patent holder of ESA-related patents and a previous employee and current consultant of Amgen Inc. The authors would like to thank Ewa Wandzioch, PhD, and Benjamin Scott, PhD (Complete Healthcare Communications, Inc.), whose work was funded by Amgen Inc., for editorial assistance.

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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Sameer Doshi
    • 1
  • Wojciech Krzyzanski
    • 2
  • Susan Yue
    • 1
  • Steven Elliott
    • 1
  • Andrew Chow
    • 1
  • Juan José Pérez-Ruixo
    • 1
    • 3
  1. 1.Amgen Inc.Thousand OaksUSA
  2. 2.State University of New York at BuffaloBuffaloUSA
  3. 3.Quantitative Pharmacology, Department of Pharmacokinetics and Drug MetabolismAmgen Inc.ValenciaSpain

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