Physiological and pharmacodynamic considerations for route of EPO administration.

Three intertwined issues--effectiveness, dosage, and route of administration--dominate discussion about recombinant human erythropoietin (rHuEPO). The major biological effect of rHuEPO is to regulate the number of committed erythroid precursors and to cause them to mature into erythrocytes. The constant presence of rHuEPO is critical to the sustenance, multiplication, and differentiation of committed erythroid progenitors that otherwise undergo apoptosis and die before they reach maturity. The route for rHuEPO administration influences the plasma concentration-time profiles. The erythropoietic response is not dependent on the peak concentration of rHuEPO achieved but on the duration of time that rHuEPO levels are maintained above a critical concentration. High levels immediately after intravenous doses are unnecessary to either induce or to sustain erythropoiesis. During the period of relative rHuEPO deficiency that invariably follows intravenous administration, committed but still rHuEPO-dependent cells undergo apoptosis and die in the bone marrow. The subcutaneous route sustains rHuEPO levels above basal levels in the interdialytic period, prevents death of rHuEPO-dependent cells, and results in more efficient and more sustained erythropoiesis. Areas under active investigation include modifications of the parent hormone and novel delivery systems that decrease elimination and maximize the residence time of rHuEPO in the circulation.