The type I interferon-alpha (IFN-alpha) family is a family of natural small proteins that have clinically important anti-infective and antitumor activity. We have developed a semisynthetic protein-polymer conjugate of IFN-alpha2b (Intron A) by attaching a 12,000-Da monomethoxypolyethylene glycol (PEG-12000) polymer to the protein. PEG conjugation is thought to increase the serum half-life and thereby prolong patient exposure to IFN-alpha2b without altering the biologic potency to the protein. Matrix-assisted laser desorption ionization/mass spectrometry (MALDI-MS), high-performance size exclusion chromatography (HPSEC), circular dichroism (CD) analysis and tryptic digestion peptide analysis of PEG Intron demonstrated that the IFN-alpha2b protein was approximately 95% monopegylated and that the primary, the secondary, and the tertiary structures were unaltered. Pegylation did not affect the epitope recognition of antibodies used for Intron A quantitation. An extensive analysis of the pegylated positional isomers revealed that approximately 50% of PEG Intron was monopegylated on the His(34) residue of the IFN-alpha2b protein. The highest antiviral activity of the pegylated positional isomers for PEG Intron was associated with the His(34) pegylated isomer. The specific activity for PEG Intron in an antiviral cytopathic protection assay was 28%, relative to Intron A. However, the potency of PEG Intron, defined as bioactivity independent of protein concentration, was comparable to Intron A at both the molecular and cellular levels in a battery of in vitro assays. Equivalent units of PEG Intron and Intron A were indistinguishable for the induction of several key IFN-induced genes, including 2',5'-oligoadenylate synthetase (2',5'-OAS) and protein kinase R (PKR), in Molt 4 cells. The antiviral dose-response curves revealed that there were no significant differences between PEG Intron and Intron A. This demonstrated that the introduction of more IFN-alpha2b protein associated with equivalent unit dosing of PEG Intron did not create any antagonism or agonism in the antiviral assay. In assays for the immune response, PEG Intron and Intron A displayed comparable potency for both natural-killer (NK) and lymphokine-activated killer (LAK) cell cytolytic activity and for the induction of class I major histocompatibility protein. These results demonstrate that PEG Intron maintains an in vitro biologic potency profile for both antiviral and immunotherapeutic activity that is highly comparable to that of Intron A.

In a three-way crossover design, 12 healthy male volunteers received 5 X 10(6) IU/m2 body surface area interferon alpha-2b(IFN alpha-2b) by intravenous (IV) infusion over 30 minutes, intramuscular (IM) injections, and subcutaneous (SC) injections. Blood and urine samples were collected at specified times, and analysis of IFN alpha-2b concentrations was performed by immunoradiometric assay. "Flulike" symptoms were the most frequently reported adverse experiences and were independent of the route of administration. After a 30-minute IV infusion, IFN alpha-2b disappeared rapidly from serum, with distribution and elimination phase half-lives of 0.1 hour and 1.7 hours, respectively. Interferon alpha-2b was absorbed slowly after IM and SC administration, with similar absorption half-lives of 5.8 and 5.5 hours, respectively. The observed maximal concentrations after IM and SC administration were 42.1 IU/mL at six hours and 45.8 IU/mL at eight hours, respectively. Interferon alpha-2b was eliminated with half-lives of 2.2 hours after IM administration and 2.9 hours after SC administration. The areas under the serum concentration-time curves for the SC and IM doses were higher than those obtained for the IV infusion. Measurable amounts of IFN alpha-2b were not found in urine regardless of the route of administration.

This analysis confirms earlier observations of progressive pharmacokinetic changes in the patients with hepatitis C during 48 weeks of treatment. The absence of a relationship between toxicity or efficacy variables and interferon concentration or activity (within a dose level) suggests that clinical management of patients (eg, for efficacy or to manage toxicity) should be based on clinically derived dosing guidelines rather than on serum concentration or activity criteria.

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Aims To assess the single-dose pharmacokinetics and tolerability of pegylated interferon-a 2b (PEG-Intron) in young and elderly healthy subjects. Methods In this parallel-design study, a single 1 m g kg -1 PEG-Intron dose was given subcutaneously to 24 subjects in the age groups 20-45, 65-69, 70-74 and 75-80 years ( n = 6/group). Blood sampling and tolerability assessments were performed up to 168 h postdose. Results The pharmacokinetic parameters were similar in all age groups. The elderly to young subject ratios for C max were 91.1, 79.5, and 107% for the 65-69 years, 70-74 years and 75-80 years groups, respectively. The corresponding values for AUC(0-• ) and CL/F were 111, 102 and 108%, and 82.5, 95.8 and 86.4%, respectively. Mean differences from the 20 to 45 years group and the 65-69 years, 70-74 years and 75-80 years groups for PEG-Intron V d/F were 108, 128 and 104%, respectively. None of these differences was statistically significant based on ANOVA .Results from a Dunnett's test (as post hoc assessment) confirmed that the pharmacokinetic parameters of Group II, Group III or Group IV were not different from those of Group I. Almost all (23/24; 96%) subjects reported typical interferon-a side-effects (flu-like symptoms, headache). One elderly patient had a myocardial infarction 12 h postdose, but recovered fully. Conclusions There are no pharmacokinetic reasons for initial dose adjustment of PEG-Intron based on age.

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