An Assessment of Recombinant Human Erythropoietin Effect on Reticulocyte Production Rate and Lifespan Distribution in Healthy Subjects

Abstract

An empirical pharmacodynamic model was developed to assess the effect of recombinant human erythropoietin (rHu-EPO) treatment on the reticulocyte production rate and lifespan distribution. Single doses of rHu-EPO at levels 20, 40, 60, 90, 120, and 160 kIU were administered to healthy volunteers (n = 8 per dose level). Erythropoietin plasma concentrations as well as hematologic responses were measured up to 42 days. The hematological data were used to determine explicit relationships between reticulocyte and red blood cell counts (RBC) and the reticulocytes' production rate and lifespan distribution. The parameter estimates obtained by simultaneous fitting of the model to the reticulocyte and RBC data revealed that rHu-EPO transiently increased the reticulocyte lifespan from the baseline value of 1.7 days to 3.4 days and the effect lasted for 8.3 days. The dose dependent increase in the reticulocyte production had the maximal value of 77.5 10(9) cells/l/day and was followed by a rebound that was less than 9% of the baseline value. Both reticulocyte and RBC responses were preceded by a dose-independent lag time of 1.7 days. The effect of rHu-EPO on the reticulocyte production rate and lifespan distribution was characterized. The results of the present study can be further utilized in building more mechanistic pharmacodynamic models of rHu-EPO stimulatory effects.