Abstract
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)-β-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-β-1a treatment induced neopterin and β2-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-β-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-β-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-β-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-β-1a was observed. These findings demonstrate that PEGylation greatly alters the pharmacokinetic properties of IFN-β-1a, resulting in an increase in systemic exposure following diverse routes of administration.
Footnotes
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Send reprint requests to: R. Blake Pepinsky, Department of Protein Chemistry, Biogen, Inc., 14 Cambridge Ctr., Cambridge, MA 02142. E-mail: Blake_Pepinsky{at}biogen.com
- Abbreviations:
- IFN
- interferon
- PEG
- polyethylene glycol
- PEGylated
- polyethylene glycol-modified
- EMC
- encephalomyocarditis
- XTT
- 2,3-bis[2-methoxy-4-nitro-5-sulfo-phenyl]-2H-tetrazolium-5-carboxyanilide
- i.t.
- intratracheal
- AUC
- area under the curve
- CL
- systemic clearance
- PAGE
- polyacrylamide gel electrophoresis
- Received January 9, 2001.
- Accepted February 18, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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