Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human EPO (rHuEPO) has biological activity in various species. This study explores the interspecies relationships of the pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO. The PK parameters such as clearance (CL) and volume of distribution (V(ss)) after i.v. doses of rHuEPO were obtained in several species via noncompartmental analysis and were assessed using the traditional allometric approach. Also, PK/PD modeling of rHuEPO concentrations and responses [reticulocytes, red blood cells (RBCs), and hemoglobin] was performed following a range of i.v. and s.c. doses in rats, monkeys, and humans. Nonlinear disposition (V(max), K(m)) and s.c. absorption rate and bioavailability parameters of rHuEPO were examined. A cascade, indirect, lifespan PD model was applied to recover efficacy (S(max)) and potency (SC(50)) of rHuEPO on erythropoiesis and erythroid cell lifespan parameters. Despite nonlinear rHuEPO disposition, CL and V(ss) were highly correlated with body weight (R(2) > 0.92) with allometric scaling exponents of 0.708 for CL and 0.853 for V(ss). The s.c. bioavailability increased with dose in monkeys and humans but appeared to be dose-independent in rats. A correlation between S(max) or SC(50) and body weight was not obvious. However, RBC lifespans obeyed allometric principles. Size dependence was found for PK and lifespan parameters, whereas pharmacologic parameters were independent of body weight.