The enigma of the metabolic fate of circulating erythropoietin (Epo) in view of the pharmacokinetics of the recombinant drugs rhEpo and NESP

Abstract

Recombinant human erythropoietin (rhEpo) is a mainstay in the treatment of anaemia, primarily in renal failure. Because the half-life of circulating rhEpo is relatively short (4-8 h), the drug is usually administered 2-3 times weekly. Recently, a novel erythropoiesis-stimulating protein (NESP) with a longer half-life (24-26 h) has been approved. NESP possesses two additional N-glycans compared to endogenous Epo or rhEpo. The pharmacokinetics of rhEpo and NESP in humans have been investigated in detail. The composition of the N-glycans is clearly important in determining the biological activity and the velocity of the degradation of Epo and its analogues. However, due to the lack of knowledge of the main site and mechanism of the removal of Epo from circulation, the difference in survival of rhEpo and NESP has remained phenomenological. Investigators have implicated the liver, kidneys, and bone marrow as possible sites of the catabolism of Epo. However, while hepatocytes take up desialylated Epo, the liver does not appear to play a major role in the degradation of intact Epo. Likewise, renal Epo clearance is apparently of secondary importance. Studies showing non-linear pharmacokinetics of Epo suggest that Epo is eliminated by saturable mechanisms. The hormone, as well as the recombinant drugs, can be incorporated by erythrocytic progenitors and other tissues expressing the Epo receptor. The affinity of the Epo receptor for rhEpo is 4.3-fold higher than for NESP. Taken together, it seems most likely that native Epo, rhEpo and NESP are degraded following Epo receptor-mediated uptake, mainly in bone marrow.