Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 48, Issue 1, Pages 43-52Publisher
WILEY
DOI: 10.1177/0091270007309702
Keywords
peptidic ERA; erythropoiesis-stimulating agents; recombinant human erythropoietin; pharmacokinetics; pharmacodynamics
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Funding
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM057980] Funding Source: NIH RePORTER
- NIGMS NIH HHS [GM 57980] Funding Source: Medline
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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 hematologicol system properties following single doses of peptidic erythropoiesis receptor agonist in normal subjects.
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