General

Interferons are a family of naturally occurring small protein molecules with molecular weights of 15,000 to 21,000 daltons that are produced and secreted by cells in response to viral infections or to various synthetic and biological inducers. Two major classes of interferons have been identified (ie type-I and type-II). Type-I interferons include a family of more than 25 interferon alphas as well as interferon beta and interferon omega. While all alpha interferons have similar biological effects, not all the activities are shared by each alpha interferon and in many cases, the extent of activity varies substantially for each interferon subtype.

All type-I interferons share common biological activities generated by binding of interferon to the cell-surface receptor, leading to the production of several interferon-stimulated gene products. Type-I interferons induce pleiotropic biologic responses which include antiviral, antiproliferative and immunomodulatory effects, regulation of cell surface major histocompatibility antigen (HLA class I and class II) expression and regulation of cytokine expression. Examples of interferon-stimulated gene products include 2'5' oligoadenylate synthetase (2'5' O.S. and ß-2 microglobulin.

The antiviral, antiproliferative, NK cell activation, and gene-induction activities of Infergen have been compared with other recombinant alfa interferons in in vitro assays and have demonstrated similar ranges of activity. Infergen exhibited at least five times higher specific activity in vitro than Interferon alfa-2a and Interferon alfa-2b.² Comparison of Infergen with a WHO international potency standard for recombinant interferon alfa (83/514) revealed that the specific activity of Infergen in both an in vitro antiviral cytopathic effect assay and an antiproliferative assay was 1 x 10⁹ units/mg. However, correlation between in vitro activity and clinical activity of any interferon is unknown.

Pharmacokinetics and Pharmacodynamics

The pharmacokinetic properties of Infergen have not been evaluated in patients with chronic hepatitis C. Pharmacokinetic profiles were evaluated in normal, healthy volunteer subjects after SC injection of 1, 3, or 9 mcg Interferon alfacon-1. Plasma levels of Infergen after SC administration of any dose were too low to be detected by either ELISA or by inhibition of viral cytopathic effect. However, analysis of Infergen-induced cellular products (induction of 2'5' OAS and ß-2 microglobulin) after treatment in these subjects revealed a statistically significant, dose-related increase in the area under the curve (AUC) for the levels of 2'5' OAS or ß-2 microglobulin induced over time (p < 0.001 for all comparisons). Concentrations of 2'5' OAS were maximal at 24 hours after dosing, while serum levels of ß-2 microglobulin appeared to reach a maximum 24 to 36 hours after dosing. The dose-response relationships observed for 2'5' OAS and ß-2 microglobulin were indicative of biological activity after SC administration of 1 to 9 mcg Infergen.

Preclinical Experience

All interferons have been shown to be highly species specific. Antiviral activity of Infergen was observed in the rhesus monkey LLC cell line and golden Syrian hamster BHK cell line. Antiviral activity of Infergen in the golden Syrian hamster was confirmed further in vivo.³ Pharmacokinetic studies of Infergen in golden Syrian hamsters and rhesus monkeys demonstrated rapid absorption following SC injection. Peak serum concentrations of Infergen were observed at 1 hour and 4 hours in golden Syrian hamsters and in rhesus monkeys, respectively. Subcutaneous bioavailability was high in both species, averaging 99% in golden Syrian hamsters and 83% to 104% in rhesus monkeys. Clearance of Infergen averaging 1.99 mL/minute/kg in golden Syrian hamsters and 0.71 to 0.92 mL/minute/kg in rhesus monkeys, was due predominantly to catabolism and excretion by the kidneys. The terminal half-life of Infergen following SC dosing was 1.3 hours in golden Syrian hamsters and 3.4 hours in rhesus monkeys. Upon 7-day multiple SC dosing, no accumulation of serum levels was observed in golden Syrian hamsters.

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