Pharmacokinetic Analysis of Continuous Erythropoietin Receptor Activator Disposition in Adult Sheep Using a Target-mediated, Physiologic Recirculation Model and a Tracer Interaction Methodology

The pharmacokinetics (PK) of continuous erythropoietin receptor activator (CERA), a PEGylated erythropoietin (EPO) derivative, was studied in sheep after bone marrow (BM) busulfan ablation by using a receptor-based recirculation model and tracer interaction method (TIM) experiments. The nontracer CERA component of the TIM was analyzed using a noncompartmental approach. In contrast to EPO elimination that is linear after the BM ablation, CERA elimination remains nonlinear. After busulfan treatment, initial EPO receptors (EPOR) normalized production rate constant, EPOR degradation rate constant, and CERA-EPOR complex internalization rate constant decreased (p < 0.01), whereas no change in CERA/EPOR equilibrium dissociation constant was detected (p > 0.05). After BM ablation, noncompartmental analysis showed that CERA-PK parameters underwent 1) a decrease in plasma clearance (p < 0.01); 2) a concomitant increase in elimination half-life and mean residence time; and 3) no significant change in volume of distribution, distribution half-life, or distributional clearance (p > 0.05). These results suggest that CERA elimination is mediated through saturable hematopoietic and nonhematopoietic EPOR pathways, with possible contribution of another EPOR-independent pathway(s). Compared with the nonhematopoietic EPOR population, the hematopoietic receptors have similar affinity to CERA but are significantly more involved in CERA's in vivo elimination. The saturable nature of the nonerythropoietic, non-BM pathway(s) for CERA in contrast to EPO predicts two fundamental differences: 1) an increasing fraction of CERA is used for erythropoiesis for increasing concentrations; and 2) the clearance of CERA becomes more limited for increasing concentrations. Taken together, these differences favor a more efficacious and prolonged action for CERA.