title: Pharmacodynamic Model of Hepcidin Regulation of Iron Homeostasis in Cynomolgus Monkeys.
abstract: Hepcidin (H25) is a hormone peptide synthesized by the liver that binds to ferroportin and blocks iron export. In this study, H25 was inhibited by administration of single and multiple doses of an anti-H25 monoclonal antibody Ab 12B9m in cynomolgus monkeys. The objective of this analysis was to develop a pharmacodynamic model describing the role of H25 in regulating iron homeostasis and the impact of hepcidin inhibition by Ab 12B9m. Total serum H25 and Ab 12B9m were determined in each animal. Corresponding measurements of serum iron and hemoglobin (Hb) were obtained. The PD model consisted of iron pools in serum (FeS), reticuloendothelial macrophages (FeM), hemoglobin (FeHb), and liver (FeL). The iron was assumed to be transported between the FeS, FeHb, and FeM unidirectionally at rates k S, k Hb, and k M. H25 serum concentrations were described by the previously developed PK model with the parameters fixed at their estimates. The serum iron and Hb data were fitted simultaneously. The corresponding estimates of the rate constants were k S/Fe0 = 0.113 h(-1), k M = 0.00191 h(-1), and k Hb = 0.00817 h(-1). The model-based IC50 value for the H25 inhibitory effect on ferroportin activity was 0.398 nM. The PD model predicted a negligible effect of Ab 12B9m on Hb levels for the tested doses. The presented PD model adequately described the serum iron time courses following single and multiple doses of Ab 12B9m. Ab 12B9m-induced inhibition of H25 resulted in a temporal increase in serum and liver iron and a decrease in the iron stored in reticuloendothelial macrophages.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA. wk@buffalo.edu.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzyzanski
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, California, USA.|Clinical Pharmacology, Clovis Oncology, San Francisco, California, USA.
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Xiao
authors.affiliation: Oncology, Amgen Inc, Thousand Oaks, California, USA.|Research Oncology, Pfizer, San Francisco, California, USA.
authors.forename: Barbra
authors.initials: B
authors.lastname: Sasu
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, California, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Hinkle
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, California, USA.|Janssen Research and Development, Beerse, Belgium.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Perez-Ruixo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D064451:Hepcidins / Q000037:antagonists & inhibitors / Q000097:blood*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007501:Iron / Q000097:blood*; D008252:Macaca fascicularis; D008954:Models, Biological
chemical_list: D000911:Antibodies, Monoclonal; D064451:Hepcidins; C545475:hepcidin 25, human; D007501:Iron
keywords: ferrokinetics; hepcidin; iron kinetics; iron-restricted erythropoiesis