A pharmacokinetics (PK)/pharmacodynamics (PD) model was developed to describe the tolerance and rebound for reticulocyte (RET) and red blood cell (RBC) counts and the hemoglobin (Hb) concentrations in blood after repeated intravenous administrations of 1350 IU/kg of recombinant human erythropoietin (rHuEPO) in rats thrice weekly for 6 weeks. Drug concentrations were described by using a quasi-equilibrium model. The PD model consisted of a lifespan-based indirect response model (LIDR) with progenitor cells [burst colony-forming unit erythroblasts and colony-forming unit erythroblasts (CFUs)], normoblasts (NOR), RETs, and RBCs. Drug-receptor complex stimulatory effects on progenitor cells differentiation and RBC lifespan were expressed by using the E(max) model (S(max-epo) and SC(50-epo), E(max) and EC(50)). The Hb profile was indirectly modeled through a LIDR model for mean corpuscular hemoglobin (with a lifespan T(mch)) including a linear (S(max-mch)) drug stimulatory effect. The negative feedback from RBCs accounted for the time-dependent rHuEPO clearance decline. A simultaneous PK/PD fitting was performed by using MATLAB-based software. PK parameters such as equilibrium dissociation, erythropoietin receptor degradation, production, and internalization rate constants were 0.18 nM (fixed), 0.08 h(-1), 0.03 nM/h, and 2.51 h(-1), respectively. The elimination rate constant and central volume of distribution were 0.57 h(-1) and 40.63 ml/kg, respectively. CFU and NOR, RET, and RBC lifespans were 37.26 h, 17.25 h, and 30.15 days, respectively. S(max-epo) and SC(50-epo) were 7.3 and 0.47 10(-2) nM, respectively. E(max) was fixed to 1. EC(50) and SC(50-epo) were equal. S(max-mch) and T(mch) were 168.1 nM(-1) and 35.15 days, respectively. The proposed PK/PD model effectively described rHuEPO nonstationary PK and allowed physiological estimates of cell lifespans.