Pharmacodynamic Model of Hepcidin Regulation of Iron Homeostasis in Cynomolgus Monkeys

Hepcidin (H-25) is a hormone peptide synthesized by the liver that binds to ferroportin and blocks iron export. In this study, H-25 was inhibited by administration of single and multiple doses of an anti-H-25 monoclonal antibody Ab 12B9m in cynomolgus monkeys. The objective of this analysis was to develop a pharmacodynamic model describing the role of H-25 in regulating iron homeostasis and the impact of hepcidin inhibition by Ab 12B9m. Total serum H-25 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 (Fe-S), reticuloendothelial macrophages (Fe-M), hemoglobin (Fe-Hb), and liver (Fe-L). The iron was assumed to be transported between the Fe-S, Fe-Hb, and Fe-M unidirectionally at rates k (S), k (Hb), and k (M). H-25 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)/Fe-0 = 0.113 h(-1), k (M) = 0.00191 h(-1), and k (Hb) = 0.00817 h(-1). The model-based IC50 value for the H-25 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 H-25 resulted in a temporal increase in serum and liver iron and a decrease in the iron stored in reticuloendothelial macrophages.