HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) All Versions of this Article: 0091270007309702v1 48/1/43    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Woo, S. Articles by Jusko, W. J. Search for Related Content PubMed PubMed Citation Articles by Woo, S. Articles by Jusko, W. J.

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

From the Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York (Dr Woo, Dr Krzyzanski, Dr Jusko); Affymax, Inc, Palo Alto, California (Dr Duliege); and BioPharma Consulting Services, Bellevue, Washington (Dr Stead).

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.

Key Words: Peptidic ERA • erythropoiesis-stimulating agents • recombinant human erythropoietin • pharmacokinetics • pharmacodynamics

Address for reprints: William J. Jusko, PhD, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 565 Hochstetter Hall, State University of New York at Buffalo, Buffalo, NY 14260; e-mail: wjjusko{at}buffalo.edu.