PT  - JOURNAL ARTICLE
AU  - R. Blake Pepinsky
AU  - Doreen J. LePage
AU  - Alan Gill
AU  - Abhijit Chakraborty
AU  - Sujata Vaidyanathan
AU  - Marie Green
AU  - Darren P. Baker
AU  - Eric Whalley
AU  - Paula S. Hochman
AU  - Pauline Martin
TI  - Improved Pharmacokinetic Properties of a Polyethylene Glycol-Modified Form of Interferon-β-1a with Preserved in Vitro Bioactivity
DP  - 2001 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1059--1066
VI  - 297
IP  - 3
4099  - http://jpet.aspetjournals.org/content/297/3/1059.short
4100  - http://jpet.aspetjournals.org/content/297/3/1059.full
SO  - J Pharmacol Exp Ther2001 Jun 01; 297
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics