Time-dependent clearance and hematological pharmacodynamics upon erythropoietin multiple dosing in rats

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) upon its repeated administrations were investigated. Two groups (A and B) of normal Wistar rats received rHuEPO intravenously at 450 or 1350 IU/kg thrice weekly for 2 and 6 weeks. PK studies were conducted following days 0 and 4 for group (A) and days 0, 17 and 28 for group (B), then, washout PK were assessed on days 11 and 36 for both groups. Reticulocytes (RET), red blood cells (RBC) and hemoglobin (Hb) were evaluated daily until day 14, then every 2 days until day 30 for group (A) and 59 for group (B). The total clearance CL(Total) increased with the dose but decreased over time. Its decay reached 20% and 55% between the first and last full PK in both treatment arms. RET peaked on day 5 and were 77.6% and 87.3% higher than baselines for the two dosing regimen. Their nadirs occurred on days 22 and 55 and were 37.9% and 47.3% below normal values. Hb peaked on days 10 and 34 and was 28.9% and 38.6% above the baseline level, its nadirs occurred on days 25 and 57 and were 13.1% and 16% below baselines. Control animals showed stable baselines over the study but with moderate variability. In conclusion, rHuEPO exhibits a nonlinear PK with a time-dependent decrease of its CL(Total). During exposure, RET, RBC and Hb showed a tolerance effect. After exposure, the rebound was characterized for RET, RBC, but not Hb.