Population pharmacokinetics and pharmacodynamics of peptidic erythropoiesis receptor agonist (ERA) in healthy volunteers.
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.
Woo
Sukyung
S
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 565 Hochstetter Hall, State University of New York at Buffalo, Buffalo, NY 14260, USA.
Krzyzanski
Wojciech
W
Duliege
Anne-Marie
AM
Stead
Richard B
RB
Jusko
William J
WJ
D000284:Administration, Oral; D000328:Adult; D000465:Algorithms; D017321:Clinical Trials, Phase I as Topic; D018849:Controlled Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004906:Erythrocyte Count; D005296:Ferrous Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D006397:Hematinics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry; D017467:Receptors, Erythropoietin / Q000819:agonists*; D012156:Reticulocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D013997:Time Factors
D005296:Ferrous Compounds; D006397:Hematinics; D006454:Hemoglobins; D010455:Peptides; D017467:Receptors, Erythropoietin; D011092:Polyethylene Glycols; C031621:ferrous fumarate