Improved pharmacokinetic properties of a polyethylene glycol-modified form of interferon-beta-1a with preserved in vitro bioactivity.
Interferon therapies suffer from a relatively short half-life of the products in circulation. To address this issue we investigated the effects of polyethylene glycol modification (PEGylation) on the pharmacokinetic properties of human interferon (IFN)-beta-1a. PEGylation with a linear 20-kDa PEG targeted at a single site on the N-terminal amine had no deleterious effect on its specific activity in an in vitro antiviral assay. In monkeys, PEG IFN-beta-1a treatment induced neopterin and beta2-microglobulin expression (pharmacodynamic markers of activity). Systemic clearance values in monkeys, rats, and mice decreased, respectively, from 232, 261, and 247 ml/h/kg for the unmodified IFN-beta-1a to 30.5, 19.2, and 18.7 ml/h/kg for the PEGylated form, while volume of distribution values decreased from 427, 280, and 328 ml/kg to 284, 173, and 150 ml/kg. The decreased clearance and volume of distribution resulted in higher serum antiviral activity in the PEG IFN-beta-1a-treated animals. In the rat, a more extensive set of dosing routes was investigated, including intraperitoneal, intratracheal, and oral administration. Bioavailability for the PEG IFN-beta-1a was similar to the unmodified protein for each of the extravascular routes examined. For the intraperitoneal route, bioavailability was almost 100%, whereas for the oral and intratracheal routes absorption was low (<5%). In rats, subcutaneous bioavailability was moderate (28%), whereas in monkeys it was approximately 100%. In all instances an improved pharmacokinetic profile for the PEGylated IFN-beta-1a was observed. These findings demonstrate that PEGylation greatly alters the pharmacokinetic properties of IFN-beta-1a, resulting in an increase in systemic exposure following diverse routes of administration.
Pepinsky
R B
RB
Biogen, Inc., Cambridge, Massachusetts, USA. Blake_Pepinsky@biogen.com
LePage
D J
DJ
Gill
A
A
Chakraborty
A
A
Vaidyanathan
S
S
Green
M
M
Baker
D P
DP
Whalley
E
E
Hochman
P S
PS
Martin
P
P
D000818:Animals; D001682:Biological Availability; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004333:Drug Administration Routes; D004591:Electrophoresis, Polyacrylamide Gel; D004686:Encephalomyocarditis virus / Q000187:drug effects / Q000254:growth & development; D005260:Female; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D007372:Interferons / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D051379:Mice; D008970:Molecular Weight; D019798:Neopterin / Q000097:blood; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D011917:Rats, Inbred Lew; D014407:Tumor Cells, Cultured; D010948:Viral Plaque Assay; D001613:beta 2-Microglobulin / Q000097:blood
D001613:beta 2-Microglobulin; D011092:Polyethylene Glycols; D019798:Neopterin; D016899:Interferon-beta; D007372:Interferons; C428112:peginterferon beta-1a; D000068556:Interferon beta-1a