J Clin Pharmacol
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First published on November 19, 2007, doi:10.1177/0091270007309702

The Journal of Clinical Pharmacology 2008;48:43.

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©© 2007 American College of Clinical Pharmacology, Inc.
The Journal of Clinical Pharmacology , 10.1177/0091270007309702

Article

Population Pharmacokinetics and Pharmacodynamics of Peptidic Erythropoiesis Receptor Agonist (ERA) in Healthy Volunteers

Sukyung Woo 1, Wojciech Krzyzanski 1, Anne-Marie Duliege 2, Richard B. Stead 3, and William J. Jusko 1*

1 State University of New York at Buffalo
2 Affymax Inc
3 BioPharma Consulting Services

* To whom correspondence should be addressed. E-mail: wjjusko{at}buffalo.edu.


  Abstract
Peptidic erythropoiesis receptor agonist is a synthetic, PEGylated peptide that can promote red blood cell production upon binding to the erythropoietin receptor. The objective of this study was to characterize the pharmacokinetics and erythropoietic effects of peptidic erythropoiesis receptor agonist in healthy volunteers. Plasma concentrations of peptidic erythropoiesis receptor agonist and pharmacodynamic responses were obtained after single intravenous injections at doses of 0.025, 0.05, and 0.1 mg/kg. Population pharmacokinetic/pharmacodynamic modeling was performed using NONMEM. Peptidic erythropoiesis receptor agonist exhibited nonlinear pharmacokinetics described by a 1-compartment model with parallel elimination by Michaelis-Menten and linear processes. A catenary, life span–based, indirect response model reflecting bone marrow erythroid and blood cells reflected the pharmacodynamics of peptidic erythropoiesis receptor agonist. A modest tolerance and rebound phenomenon in reticulocytes was modeled with negative feedback regulation related to hemoglobin. This pharmacokinetic/ pharmacodynamic model well characterized the prolonged disposition, intrinsic pharmacologic parameters, and typical hematological system properties following single doses of peptidic erythropoiesis receptor agonist in normal subjects.
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