General

Interferons are a family of naturally occurring proteins, which have molecular weights ranging from 15,000 to 21,000 daltons. Three major classes of interferons have been identified: alfa, beta, and gamma. Interferon beta-1b, interferon alfa, and interferon gamma have overlapping yet distinct biologic activities.^1-5 The activities of Interferon beta-1b are species-restricted and therefore, the most pertinent pharmacologic information on Betaseron is derived from studies of human cells in culture and in humans.

Biologic Activities

Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities. The mechanisms by which Betaseron exerts its actions in multiple sclerosis (MS) are not clearly understood. However, it is known that the biologic response-modifying properties of Interferon beta-1b are mediated through its interactions with specific cell receptors found on the surface of human cells. The binding of Interferon beta-1b to these receptors induces the expression of a number of interferon-induced gene products (e.g., 2',5'-oligoadenylate synthetase, protein kinase, and indoleamine 2,3-dioxygenase) that are believed to be the mediators of the biological actions of Interferon beta-1b.^1,3,6-10 A number of these interferon-induced products have been readily measured in the serum and cellular fractions of blood collected from patients treated with Interferon beta-1b.^11,12

Pharmacokinetics

Because serum concentrations of Interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less of Betaseron, pharmacokinetic information in patients with MS receiving the recommended dose of Betaseron is not available. Following single and multiple daily subcutaneous administrations of 0.5 mg Betaseron to healthy volunteers (N=12), serum Interferon beta-1b concentrations were generally below 100 IU/mL. Peak serum Interferon beta-1b concentrations occurred between 1 to 8 hours, with a mean peak serum interferon concentration of 40 IU/mL. Bioavailability, based on a total dose of 0.5 mg Betaseron given as two subcutaneous injections at different sites, was approximately 50%.

After intravenous administration of Betaseron (0.006 mg to 2.0 mg), similar pharmacokinetic profiles were obtained from healthy volunteers (N=12) and from patients with diseases other than MS (N=142). In patients receiving single intravenous doses up to 2.0 mg, increases in serum concentrations were dose proportional. Mean serum clearance values ranged from 9.4 mL/min·kg^-1 to 28.9 mL/min·kg^-1 and were independent of dose. Mean terminal elimination half-life values ranged from 8.0 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 L/kg to 2.88 L/kg. Three-times-a-week intravenous dosing for 2 weeks resulted in no accumulation of Interferon beta-1b in the serum of patients. Pharmacokinetic parameters after single and multiple intravenous doses of Betaseron were comparable.

Clinical Trials

The effectiveness of Betaseron in relapsing-remitting MS was evaluated in a double-blind, multiclinic (11 sites: 4 Canadian and 7 United States), randomized, parallel, placebo-controlled clinical investigation of 2 years duration. The study enrolled MS patients, aged 18 to 50, who were ambulatory (Kurtzke expanded disability status scale [EDSS] of less than or equal to 5.5), exhibited a relapsing-remitting clinical course, met Poser's criteria¹³ for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over 2 years preceding the trial without exacerbation in the preceding month. Patients who had received prior immunosuppressant therapy were excluded.

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