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Population Pharmacokinetics and Pharmacodynamics of Peptidic Erythropoiesis Receptor Agonist (ERA) in Healthy Volunteers
Author(s) -
Woo Sukyung,
Krzyzanski Wojciech,
Duliege AnneMarie,
Stead Richar B.,
Jusko Willia J.
Publication year - 2008
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270007309702
Subject(s) - agonist , erythropoiesis , pharmacokinetics , pharmacodynamics , pharmacology , erythropoietin , population , receptor , medicine , endocrinology , anemia , environmental health
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.