Interferon beta-1b serum levels in multiple sclerosis patients following subcutaneous administration

Abstract

Recombinant interferon beta-1b (rIFNbeta) reduces the frequency of exacerbations in relapsing-remitting MS when administered subcutaneously on alternate days. However, the pharmacokinetics of rIFNbeta are not well understood and there are scant data on the detectability of rIFNbeta in the serum of MS patients following subcutaneous administration. Moreover, existing assays for detecting IFNbeta are biologic, time-consuming, and require handling of infectious agents. We developed and standardized an ELISA specific for measuring rIFNbeta with a detection range of 40 to 1,000 IU/ml. The specificity of our ELISA was confirmed by the lack of cross-reactivity with other cytokines, including IFNalpha, IFNgamma, IFN Consensus-1, and TNFalpha. We screened serum from 34 MS patients drawn within 12-36 hours of treatment: 15 patients taking 8 MIU, four patients taking 1.6 MIU, and 15 patients taking placebo. Eleven of the 15 patients in the 8-MIU treatment group had measurable rIFNbeta serum levels ranging from 120 to 475 MIU/ml. Two of four patients in the 1.6-MIU treatment group, but none of the placebo group, had detectable serum rIFNbeta levels. A small prospective time-course study was carried out in four MS patients receiving rIFNbeta. Serial blood samples were obtained prior to and 4, 8, 24, and 48 hours after rIFNbeta injection. A peak serum rIFNbeta level was observed between 8 and 24 hours after rIFNbeta injection and tended to decline to near preinjection levels at 48 hours postinjection. These results are consistent with the rationale of alternate-day, subcutaneous administration of rIFN beta. In addition, the ELISA described might be a useful tool to study the pharmacokinetics and the relationship of rIFN beta serum levels to clinical efficacy.

IFN-β-1b Inhibits IL-12 Production in Peripheral Blood Mononuclear Cells in an IL-10-Dependent Mechanism: Relevance to IFN-β-1b Therapeutic Effects in Multiple Sclerosis

“…The inhibitory effect of IFN-␤-1b on inducible IL-12 was observed at doses as low as 10 and 100 IU/ml. These doses are well within the expected range for IFN-␤ blood levels when administered therapeutically to humans (31), suggesting that this inhibitory effect could be biologically significant in vivo.…”

Interferons in enteroviral heart disease: modulation of cytokine expression and antiviral activity

“…However, only very low plasma concentrations (<5 IU/ml) were observed after s.c. injection of natural and recombinant IFN-b, as most of the injected interferon remains at the injection side or is distributed through the lymphatic route [3,7,33]. A single study with contradictory results on the pharmacokinetics of recombinant IFN-b expressed in E. coli (IFN-b 1b) suggested sufficient blood concentrations (>100 IU/ml) after s.c. application of a comparatively high dose of 8·10 6 IU, but these results need confirmation [23]. Probably, IFN-b will not reach the heart tissue in adequate concentrations for antiviral activity after s.c. injection.…”

Management of women with multiple sclerosis through pregnancy and after childbirth

“…After injection, serum levels peak between 8 to 24 hours, then decline [Khan et al 1996]. Interferon beta is not believed to cross the placenta; a sister type-1 interferon (alpha) was shown by two assays not to penetrate placental tissue [Waysbort et al 1993].…”