Receptor-based model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics

Objective, Previous clinical studies have demonstrated two distinctive phar macokinetic behaviors of erythropoietin (EPO): changes in pharmacokinetics (PK) after a period of rhEPO treatment and nonlinear pharmacokinetics. The objective of this work was to study the temporal changes in EPO's PK follow ing phlebotomy in order to propose possible mechanisms for this behavior. Methods. Five healthy adult sheep were phlebotomized on two separate occasi ons 4-6 weeks apart to hemoglobin levels of 3-4 g/dL, PK parameters mere es timated from the concentration time profiles obtained following repeated in travenous bolus PK studies using tracer doses of biologically active I-125- rhEPO. Based on the changes in clearances, a PK model was derived to provid e a mechanistic receptor-based description of the observed phenomena. Results. Phlebotomy resulted in a rapid increase in the EPO plasma concentr ation, which peaked at 760 +/- 430 mU/mL (mean +/- SD) at 1.8 +/- 0.65 days , and which coincided with a transient reduction in EPO clearance from prep hlebotomy values, i.e., from 45.6 +/- 11.2 mL/ hr/Kg to 24.3 +/- 9.7 mL/hr/ kg. As plasma EPO levels returned toward baseline levels in the next few da ys, a subsequent increase in EPO clearance was noted. EPO clearance peaked at 90.2 +/- 26.2 mL/hr/kg at 8.5 +/- 3.3 days and returned to baseline by 4 -5 weeks postphlebotomy, The proposed model derived from these data include s positive feedback control of the EPO receptor (EPOR) pool. Conclusion. The model predicts that: 1) the initial reduction in EPO plasma clearance is due to a transient saturation of EPORs resulting from the phl ebotomy-induced high EPO concentration; and 2) the EPOR pool is expandable not only to compensate for EPOR loss but also to adjust to a greater need f or EPORs/progenitor cells to restore hemoglobin (Hb) concentration to norma l levels. (C) 2001 International Society for Experimental Hematology, Publi shed by Elsevier Science Inc.