An integrated pharmacodynamic analysis of erythropoietin, reticulocyte, and hemoglobin responses in acute anemia.

PURPOSE: To determine by pharmacodynamic (PD) analysis physiologically relevant parameters of the cellular kinetics of erythropoiesis in acute anemia.

METHODS: The PD relationships among erythropoietin (EPO), reticulocyte, and RBC (Hb) responses were investigated in young adult sheep in acute anemia induced twice by two controlled phlebotomies separated by a 4-week recovery period.

RESULTS: The phlebotomies resulted in rapid increases in plasma EPO, with maximal levels occurring at 3 to 8 days, followed by a reticulocyte response with a delay of 0.5 to 1.5 days. The Hb returned to prephlebotomy base line at the end of the 4-week recovery period. The EPO, reticulocyte count, and Hb responses were well described by a PK/PD model (r = 0.975) with the following cellular kinetics parameters: the lag time between EPO activation of erythroid progenitor cells and reticulocyte formation; the reticulocyte-to-RBC maturation time; the reticulocyte and Hb formation efficacy coefficients, quantifying EPO's efficacy in stimulating the formation of reticulocytes and Hb, respectively; the C50 PK/PD transduction parameter defined as the EPO level resulting in half the maximum rate of erythropoiesis.

CONCLUSION: Physiologically relevant cellular kinetics parameters can be obtained by an endogenous PK/PD analysis of phlebotomy data and are useful for elucidating the pathophysiologic etiology of various anemias.