Interferon beta-1a exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2'/5'-oligoadenylate synthetase, β2-microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1a. After a single intramuscular dose of interferon beta-1a, serum levels of these products remain elevated for at least four days and up to one week.
Whether the mechanism of action of interferon beta-1a in MS is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of MS is not well established.
Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta are classified as Type I interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis.
Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and interferon beta-1a are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined.
The pharmacokinetic profile of interferon beta-1a has been investigated indirectly with an assay that measures interferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative assay techniques are not sufficiently sensitive.
Following intramuscular administration of interferon beta-1a, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Subcutaneous administration cannot be substituted for intramuscular administration.
No carcinogenicity data for interferon beta-1a are available in animals or humans.
In a 26-week repeated dose toxicity study in rhesus monkeys by intramuscular route once per week, administered in combination with another immunomodulating agent, an anti CD40 ligand monoclonal antibody, no immune response toward interferon beta-1a and no signs of toxicity were demonstrated.
Intramuscular irritation has not been evaluated in animals following repeated administration to the same injection site.
Limited but relevant mutagenesis tests have been carried out. The results have been negative.
Fertility and developmental studies in rhesus monkeys have been carried out with a related form of interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed. Similar reproductive dose-related effects have also been observed with other forms of alpha and beta interferons. No teratogenic effects or effects on foetal development have been observed, but the available information on the effects of interferon beta-1a in the peri- and post-natal periods is limited.
No information is available on the effects of interferon beta-1a on male fertility.
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