A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for recombinant human erythropoietin (rHuEPO) to account for receptor-mediated endocytosis via erythropoietin receptor (EPOR) as a primary mechanism for nonlinear disposition of rHuEPO as well as activation of erythropoietic stimulation. Time profiles of rHuEPO concentrations following a wide range of intravenous (i.v.) doses in rats (10, 100, 450, 1,350, 4,050 IU/kg), monkeys (500, 2,000, 4,000 IU/kg), and man (10, 100, 150, 300, 500 IU/kg) were examined. The mean data of reticulocytes, red blood cells (RBC), and hemoglobin for five different doses in rats were analyzed. The PK model components included receptor binding, subsequent internalization and degradation, EPOR turnover, non-specific tissue distribution, and linear first-order elimination from plasma. The equilibrium dissociation constant (K ( D )) was similar between rats and monkeys (0.11 nM) and was 10-fold lower in humans (0.012 nM). The PD effects of rHuEPO were described by an indirect response model with lifespan cell loss and driven by the rHuEPO-EPOR complex. A generalized nonlinear PK model for rHuEPO taking into account EPOR binding of the drug in bone marrow was proposed and well described the PK profiles of rHuEPO following i.v. doses in rats, monkeys, and man. The present receptor-mediated PK/PD model for rHuEPO closely reflects underlying mechanisms of disposition and dynamics of rHuEPO.