Polyethylene glycol modification of filgrastim results in decreased renal clearance of the protein in rats.
This report provides the evidence that pegfilgrastim, which is produced by covalently binding a 20-kDa polyethylene glycol molecule to filgrastim, has decreased renal clearance compared with the native protein, filgrastim. After intravenous administration, the area under the plasma concentration versus time curve values for pegfilgrastim were significantly higher than those for filgrastim, indicating that the clearance was slower for pegfilgrastim. The concentration-time profiles of pegfilgrastim were similar between sham-operated and bilateral nephrectomized rats, suggesting that the kidney had an insignificant role in the elimination of pegfilgrastim. In contrast, bilateral nephrectomy resulted in decreased clearance of filgrastim by 60-75%. These data are consistent with the current knowledge that pegylation of proteins decreases the renal clearance of these conjugated proteins.
Yang
Bing-Bing
BB
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. byang@amgen.com
Lum
Peggy K
PK
Hayashi
Michael M
MM
Roskos
Lorin K
LK
D000818:Animals; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D000069585:Filgrastim