AI Article Synopsis
- Erythropoietin (EPO) receptor-mediated endocytosis and degradation is thought to be the main way erythropoiesis-stimulating agents (ESAs) are cleared from the body.
- The study examined how various forms of recombinant human EPO (rHuEPO) differ in their clearance rates when given intravenously to rats and mice, focusing on rHuEPO derivatives with varying receptor binding activities and carbohydrate content.
- Findings indicate that ESAs with more carbohydrates or polyethylene glycol (PEG) have longer half-lives and slower clearance rates mainly due to their reduced elimination by receptor-independent pathways.
Article Abstract
Erythropoietin (EPO) receptor-mediated endocytosis and degradation in the bone marrow has been hypothesized to be the major clearance pathway of erythropoiesis-stimulating agents (ESA). We investigated the role of this pathway in ESA clearance by determining the pharmacokinetic profiles after intravenous (IV) dosing in rats and mice of recombinant human EPO (rHuEPO) and rHuEPO derivatives with different receptor binding activities and biochemical properties. These derivatives included NM385 (no detectable receptor binding activity), hyperglycosylated analogs with different carbohydrate contents and receptor binding activities; (NM294: +1 carbohydrate chain; darbepoetin alfa: +2 carbohydrate chains) and polyethylene glycol (PEG) derivatives (PEG-darbepoetin alfa, PEG-rHuEPO and PEG-NM385). After IV administration in rats, NM385 had a mean clearance (CL) similar to rHuEPO. Hyperglycosylated ESAs, compared with rHuEPO, had a progressively longer half-life (t(1/2)) and a progressively slower CL with increasing number of carbohydrates or amount of added PEG that correlated more closely with carbohydrate and/or PEG content than receptor binding activity. Taken together, these results suggest that (1) EPO receptor-independent pathway(s) play a substantial role in ESA clearance; (2) the longer half-life and reduced clearance of hyperglycosylated and/or PEGylated ESAs are primarily the result of decreased susceptibility to receptor-independent elimination mechanisms.
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| http://dx.doi.org/10.1002/jps.21578 | DOI Listing |
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