Clinical Pharmacokinetics and Pharmacodynamics of Erythropoiesis-Stimulating Agents

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.