these effective concentrations would lead to the best efficacy profile . Proof-of-concept studies could be performed in healthy subjects19 by measuring the pegylated IFN-stimulation of effector proteins. Certain physico-chemical properties associated with PEG size and structure and the stability of the bond between the PEG moiety and IFN could lead to a molecule that exhibited sustained concentrations but no measureable in vitro activity. Thus, a balance between the in vitro potency and the in vivo properties of a pegylated IFN needed to be achieved. Preclinical work

Figure 3. Multidimensional Approach used to Optimize Pegylation of Interferon alfa-2a

ensured that the selected pegylated IFN retained the antiviral, immunomodulatory and antiproliferative properties that are associated with IFN alfa-2a20.

Pharmacokinetic studies in rats using conjugates of IFN alfa-2a with PEG moieties of varying molecular weights and different structures (branched and linear), including three linear (5, 20 and 40 KD) and two branched (20 and 40 KD) PEG moieties showed that the absorption of the pegylated IFNwas more sustained, the distribution more restricted and the clearance reduced as the size of the PEG moiety increased21.

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