Enteral bioavailability of human granulocyte colony stimulating factor conjugated with poly(ethylene glycol).
OBJECTIVE
The focus of this paper is to demonstrate that pegylation of a therapeutic protein, recombinant human granulocyte colony stimulating factor (PEG-G-CSF), results in an increase in stability and in retention of in vivo bioactivity when administered by the intraduodenal route and may, therefore, be a suitable form of the protein for inclusion in an oral delivery formulation.


METHODS
The ability of PEG-G-CSF to elicit a therapeutic response from the enteral route was investigated by two methods of intraduodenal dosing in an in vivo model to determine the optimal dosing method: by slow, constant infusion, or by a single bolus administration.


RESULTS
Circulating levels of the proteins confirmed that PEG-G-CSF was delivered into the systemic circulation from the enteral route and that biological activity was retained. Bioavailability from the enteral route by the constant infusion method was calculated from the intravenous administration of the proteins to be between 1.8 and 3.5% while un-modified G-CSF failed to elicit a quantifiable response by this method. Bolus administration of PEG-G-CSF also resulted in biological activity although responses were short lived and significantly lower than with the pegylated formulation.


CONCLUSIONS
The possible mechanisms of enteral delivery of PEG-G-CSF are discussed. Our results indicate that oral delivery of pegylated G-CSF may be possible and in fact, preferable to using the un-modified form of the therapeutic.
Jensen-Pippo
K E
KE
Department of Pharmacology, Amgen Inc., Thousand Oaks, California 91320, USA.
Whitcomb
K L
KL
DePrince
R B
RB
Ralph
L
L
Habberfield
A D
AD
D000818:Animals; D001682:Biological Availability; D004386:Duodenum / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D007263:Infusions, Parenteral; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols