Investigation of the effects of altered receptor binding activity on the clearance of erythropoiesis-stimulating proteins: Nonerythropoietin receptor-mediated pathways may play a major role.
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.
Agoram
Balaji
B
Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA.
Aoki
Ken
K
Doshi
Sameer
S
Gegg
Colin
C
Jang
Graham
G
Molineux
Graham
G
Narhi
Linda
L
Elliott
Steve
S
D000818:Animals; D002460:Cell Line; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006397:Hematinics / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D011994:Recombinant Proteins
D006397:Hematinics; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin