Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07.

Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and antiproliferative properties.

Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore glycosylated like the natural protein.

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 2’5’OAS synthetase and serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to decline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable responses. After repeated subcutaneous administration every 48 hours for 4 doses, these biological responses remain elevated, with no signs of tolerance development.

Biological response markers (e.g., 2',5'-OAS activity, neopterin and beta 2- microglobulin) are induced by interferon beta-1a following subcutaneous doses administered to healthy volunteer subjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hours for neopterin, beta-2-microglobulin and 2',5'OAS, 12 hours for MX1 and 24 hours for OAS1 and OAS2 gene expression.
Peaks of similar height and time were observed for most of these markers after first and sixth administration.

The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.


Single clinical event suggestive of multiple sclerosis

One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical event suggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that could better explain signs and symptoms of the patient had to be excluded.

Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three times per week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating event occurred confirming definite multiple sclerosis, patients switched to the recommended posology of Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as to initial randomisation.

Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from this study are as follows:

Parameter           Treatment                     Treatment Comparison Statistics                                        Rebif 44 mcg tiw versus Placebo Placebo      Rebif 44           Risk         Cox’s      Log-Rank (n=171)      mcg tiw         Reduction   Proportional    p-value (n=171)                     Hazard Ratio
[95% CI]
McDonald (2005) Conversion
Number of events        144            106                        0.49 51%                     <0.001
KM Estimate           85.8%         62.5%                     [0.38;0.64] 
CDMS Conversion
Number of events        60             33                         0.48 52%                     <0.001
KM Estimate           37.5%         20.6%                     [0.31;0.73] 
Mean CUA Lesions per Subject per Scan During the Double Blind Period Least Square                                                      0.19 2.59 (0.30)   0.50 (0.06)        81%                     <0.001 Means (SE)                                                    [0.14;0.26]* tiw: three times per week, CI: confidence interval, CUA: combined unique active * Least Squared Mean Ratio [95% CI]

For the time being there is no well established definition of a high risk patient, although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the initial scan. In any case, treatment should only be considered for patients classified as high risk.

Relapsing-remitting multiple sclerosis

The safety and efficacy of Rebif has been evaluated in patients with relapsing- remitting multiple sclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously three times per week. At licensed posology, Rebif 22/44 micrograms 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 EDSS of 0-5.0 at entry. The proportion of patients with disability progression, as defined by at least one point increase in EDSS confirmed three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms) and was reduced from 39% (placebo) to 27% (Rebif 44 micrograms). Over 4 years, the reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 29% in patients treated with Rebif 44 micrograms group compared with a group of patients treated with placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years.

Secondary progressive multiple sclerosis

In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3- 6.5) with evidence of clinical progression in the preceding two 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%. If 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 micrograms and 44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be interpreted cautiously.

Primary progressive multiple sclerosis

Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should not be used in these patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp multi-exponential decline, with serum levels proportional to the dose.
Subcutaneous and intramuscular administrations of Rebif produce equivalent exposure to interferon beta.

Distribution

Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum concentrations were typically observed after 8 hours, but this was highly variable.

Elimination

After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple dosing.

Metabolism

Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys.