Erythropoietin is a hematopoietic growth factor stimulating the production ofRBC.Erythropoiesis-stimulating agents (ESAs) have been indicated for treatment of anemia associated with renal failure,cancer chemotherapy,and HIV antiviral therapy.Apart from ESAs stimualting hypoxia inducible factor 1α the major mechanism of action for ESAs is binding and activation of erythropoieting receptor expressed on erythroid progenitor cells.Recombinant human erythropoietin (rHuEPO) is derived from a cloned human EPO gene and it has the natural 165 amino acid sequence but differs in glycosylation pattern.It has a circulation half-life of 7 h with a binding affinity of KD=60 pM.Darbepoetin alfa (NESP) is a glycosylation analog of rHuEPO with two additional N-linked carbohydrates.NESP serum half-life is 25 h and the dissociation constant is 400 pM,yet its in vivo activity is greater than one of rHuEPO.This phenomenon can be explained by the minimum effective concentration (MEC) hypothesis.The system pharmacology approach applied to the concentration-effect relationships for these ESAs allows one to identify the determinants of their efficacy.The prolonged exposure maintaining ESA plasma concentration above the MEC level is more effective than an increased affinity for EPOR.These conclusions apply to of newly developed ESAs and imply potential improvements of existing therapies.