Differential pharmacokinetic analysis of in vivo erythropoietin receptor interaction with erythropoietin and continuous erythropoietin receptor activator in sheep

摘要

The two erythropoiesis stimulating agents (ESAs), short acting recombinant human erythropoietin (EPO) and long acting continuous erythropoietin receptor activator (CERA), have been hypothesized to share an in vivo elimination pathway that involves binding to erythropoietin receptor (EPOR) and subsequent internalization. A physiologically based recirculation model and a pharmacokinetic tracer interaction methodology (TIM) were used to compare the in vivo interaction kinetics with EPOR between the two ESAs in adult sheep. Animals treated with EPO experienced a greater EPOR up-regulation than those treated with CERA, as evidenced by an eightfold-higher initial EPOR normalized production rate constant, ksyn/R0, versus a twofold-larger EPOR degradation rate constant, kdeg. In agreement with in vitro studies, EPO had a lower in vivo equilibrium dissociation constant from EPOR than CERA (KD = 6 versus 88.4 pmol/l, respectively, p < 0.01). The internalization and/or degradation of the EPO–EPOR complex was faster than that of the CERA–EPOR complex (kint = 24 versus 2.41 h⁻¹, respectively, p < 0.01). The adopted model enables a mechanism-based explanation for CERA’s slower elimination and greater erythropoietic activity in vivo. As predicted by the model, the slower elimination of CERA is due to: (1) less EPOR up-regulation induced by CERA administration; (2) slower binding of CERA to EPOR; and (3) reduced internalization and/or degradation rate of surface-bound CERA. Slower CERA/EPOR complex elimination explains the greater in vivo erythropoiesis reported for CERA, despite its lower affinity to EPOR. A sensitivity analysis showed that the model parameters were reliably estimated using the TIM methodology.