Pharmacodynamic analysis of stress erythropoiesis: change in erythropoietin receptor pool size following double phlebotomies in sheep.

A feedback receptor regulation model was incorporated into a pharmacodynamic model to describe the stimulation of hemoglobin (Hb) production by endogenous erythropoietin (EPO). The model considers the dynamic changes that take place in the EPO receptor (EPOR) pool under phlebotomy-induced anemia. Using a (125)I-rhEPO tracer the EPO clearance changes are evaluated longitudinally prior to and following phlebotomy-induced anemia indirectly to evaluate changes in the EPOR pool size, which has been shown to be linearly related to the clearance. The proposed model simultaneously captures the general behavior of temporal changes in Hb relative to EPO plasma clearance in five lambs (r = 0.95), while accounting for the confounding variables of phlebotomy and changes in the blood volume in the growing animals. The results indicate that under anemia the EPOR pool size is up-regulated by a factor of nearly two over baseline and that the lowest and highest EPOR pool sizes differ by a factor of approximately four. The kinetic model developed and the data-driven mechanism proposed serves as a starting point for developing an optimal EPO dosing algorithm for the treatment of neonatal anemia.