Rebif Mechanism of Action

Pharmacotherapeutic Group: Cytokines. ATC Code: L03AB.
Pharmacology: Pharmacodynamics: Interferons (IFNs) are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and antiproliferative properties.
Rebif (interferon-β_1a) is composed of the native amino acid sequence of natural human interferon-β. It is produced in mammalian cells (Chinese hamster ovary) and is therefore glycosylated like the natural protein.
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.
The safety and efficacy of Rebif have been evaluated in patients with relapsing-remitting multiple sclerosis at doses ranging from 11-44 mcg (3-12 MIU) administered SC 3 times/week. At licensed posology, Rebif has been demonstrated to decrease the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at least 2 exacerbations in the previous 2 years and with an expaned disability status state (EDSS) of 0-5 at entry. The proportion of patients with disability progression, as defined by at least 1 point increase in EDSS confirmed 3 months later, was reduced from 39% (placebo) to 30% (Rebif 22 mcg) and 27% (Rebif 44 mcg). Over 4 years, the reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 mcg and 29% in patients treated with Rebif 44 mcg compared with a group of patients treated with placebo for 2 years and then either Rebif 22 or 44 mcg for 2 years.
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence of clinical progression in the preceding 2 years and who had not experienced relapses in the preceding 8 weeks, Rebif had no significant effect on progression of disability but relapse rate was reduced by approximately 30%. The patient population was divided into 2 subgroups (those with and those without relapses in the 2-year period prior to study entry). There was no effect on disability in patients without relapses, but in patients with relapses, the proportion with progression in disability at the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 and 44 mcg combined). These results obtained in a subgroup of patients, a posteriori, should be interpreted cautiously.
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should not be used in such patient.
Pharmacokinetics: In healthy volunteers after IV administration, interferon-β_1a exhibits a sharp multiexponential decline with serum levels proportional to the dose. The initial half-life is in the order of min and the terminal half-life is several hrs, with the possible presence of a deep compartment. When administered by the SC or IM routes, serum levels of interferon-β remain low, but are still measurable up to 12-24 hrs post-dose. SC and IM administrations of Rebif produce equivalent exposure to interferon-β. Following a single 60-mcg dose, the maximum peak concentration, as measured by immunoassay, is around 6-10 IU/mL, occurring on average of around 3 hrs after the dose. After SC administration at the same dose repeated every 48 hrs for 4 doses, a moderate accumulation occurs [about 2.5 times for area under the curve (AUC)].
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the administration of Rebif. After a single dose, intracellular and serum activity of 2-5A synthetase and serum concentrations of β₂-microglobulin and neopterin increase within 24 hrs, and start to decline within 2 days. IM and SC administrations produce fully superimposable responses. After repeated SC administration every 48 hrs for 4 doses, these biological responses remain elevated, with no signs of tolerance development.
Interferon-β_1a is mainly metabolised and excreted by the liver and by the kidneys.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, and genotoxicity.
Rebif has not been investigated for carcinogenicity.
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. Based on observations with other α- and β-interferons, an increased risk of abortions cannot be excluded. No information is available on the effects of the interferon-β_1a on male fertility.