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Vol. 297, Issue 3, 1059-1066, June 2001

Improved Pharmacokinetic Properties of a Polyethylene Glycol-Modified Form of Interferon-beta -1a with Preserved in Vitro Bioactivity

R. Blake Pepinsky, Doreen J. LePage, Alan Gill, Abhijit Chakraborty, Sujata Vaidyanathan, Marie Green, Darren P. Baker, Eric Whalley, Paula S. Hochman and Pauline Martin

Biogen, Inc., Cambridge, Massachusetts

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 beta 2-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.

0022-3565/01/2973-1059$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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