A pharmacodynamic analysis of erythropoietin-stimulated reticulocyte response in phlebotomized sheep

The pharmacodynamics (PD) of the reticulocyte response resulting from phleb otomy-induced erythropoietin (EPO) was investigated in adult sheep. The ane mia caused by the controlled phlebotomy (Hb, < 4 g/dl, t = 0) resulted in a rapid increase in EPO with peak concentrations from 200 to 1400 mU/ml at 0 .5 to 3 days generating a delayed reticulocyte response with peak levels fr om 9.3 to 14.1% at 2.5 to 5.1 days. The PD EPO-reticulocyte relationship is well described by a simple kinetic model involving 3 relevant physiologic parameters: T-1 = lag-time (0.73 +/- 0.32 days, mean +/- S.D.), T-2 = retic ulocyte maturation time (5.61 +/- 1.41 days), and k = EPO efficacy coeffici ent (0.052 +/- 0.048% g/dl mU/ml/day). Accordingly, 0.52% reticulocytes at 10 g/dl Hb level are generated per day at an EPO concentration of 100 mU/ml . The difference between the T-2 parameter in this study and the maturation time reported for humans may be due to interspecies differences or differe nt technique and experimental conditions. The PD transduction appears large ly linear in the observed EPO concentration range, indicating a full utiliz ation of EPO without any significant PD saturation. Also, the EPO concentra tion versus time profiles resulting from the phlebotomy were similar to exo genous EPO profiles resulting from s.c. therapeutic dosing. This study supp orts the hypothesis that s.c. EPO dosing is more efficacious than i.v. dosi ng.