Bio equivalence of Two Subcutaneous Pharmaceutical Products of Interferon Beta la

Abstract

Blastoferon, in the following referred to as the test product, is a pharmaceutical product of interferon beta la (CAS 220581-49-7) currently marketed as a biosimilar to the innovator Interferon beta la product (referred to as the reference product). Pharmacokinetics and pharmacodynamIcs assays are critically relevant to demonstrate similarity between biopharmaceuticals. The aims of the present study were to investigate the bioavailability (BA) of the test product (either absolute or relative to the innovator product) and to compare the extent of increase of neopterin concentration following administration of either product. Two studies were performed: initially, an absolute BA assay with i.v. and s.c. injection of test product to 12 healthy subjects. Second, a formal relative BA study with s.c. injections of 88 microg of both products to 24 healthy volunteers. Blood samples for pharmacokinetic and pharmacodynamic profiling were drawn at different intervals after injection. Interferon beta (IFNB) concentrations were determined by ELISA. In the absolute BA study, a single s.c. dose of 44 microg of the test product resulted in a median bioavailable fraction of 29%, a median T(max) of 4 h (4-6) and a C(max) of 3.69 (3.27-4.41) IU x ml(-1). In the relative BA study, values for the test product were: median T(max) of 3 h (2-18), C(max) of 5.39 (4.99-6.31) IU x ml(-1), AUC (0-72) of 142.86 (134.16-190.15) IU x h x ml(-1) and AUC(0-infinity) of 190.95 (174.23-303.13) IU x h x ml(-1). The corresponding values for the innovator product were: T(max) of 3 h (1-24), C(max) of 4.44 (4.12-5.40) IU x ml(-1), AUC(0-72) of 128.77 (121.18-170.92) IU x h x ml(-1) and AUC(0-affinity) of 192.61 (183.04-286.46) IU x h x ml(-1). The AUC(0-72) ratio was 111% (CI 90%: 106-116), the AUC(0-affinity) was 99% (CI 90%: 92-107) and the C(max) ratio was 121% (CI 90%: 112-131). IFNB1a increased neopterin levels in both studies. Both products induced side-effects commonly reported for IFN with no serious adverse events. This study presents pharmacokinetics parameters of the test product and demonstrates similar bioavailability of IFNB1a for both pharmaceutical products.

Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-β

“…The rationale is that lymphatic capillaries compared to blood capillaries have a higher permeability for greater proteins due to the absence of a basement membrane and the presence of clefts between endothelial cells [24]. Bioavailability of IM and SC applied IFNb is~30% [25][26][27][28][29] and does not differ between these routes of administration [26,27]. We are not aware of studies having investigated the influence of dose and concentration of IFNb on bioavailability; however, a direct correlation between dose and IFNb serum concentrations has been observed in subjects receiving PEG-IFNb-1a [30].…”

“…Eventually, IM and SC administration of IFNb exhibit protracted absorption, which results in peak plasma concentrations after several hours [25][26][27][28][29][32][33][34][35][36][37]. IFNb concentrations are detectable for~1 --2 days after injection and, therefore, for a longer time period than after intravenous (IV) administration [25,29,32,33,37].…”

“…IFNb concentrations are detectable for~1 --2 days after injection and, therefore, for a longer time period than after intravenous (IV) administration [25,29,32,33,37]. Peak serum concentrations (C max ) following IM or SC route of administration are significantly lower than after an equal IV dose [25,26,28,29]. The slow release of IFNb from the injection site could explain the long apparent half-life of IM and SC administered IFNb [38].…”

“…After IV administration (as bolus injection) serum IFNb concentrations peak within 5 min [27,28], then decline rapidly in a bi- [27][28][29] or multi-exponential [25,26] manner with a half-life of approximately 4 h [25,[27][28][29]. Serum concentrations are measureable for up to 8 h after IV administration [27,28].…”

“…Whereas IFNb serum levels peak early after administration (within minutes after IV [26][27][28] and several hours after SC or IM injection [25][26][27][28][29][32][33][34][35][36][37]), the classical PD markers (see above) peak after approximately 24 h [26][27][28][29]35] up to 48 h [34,36,37]. With continuous therapy, there are also late IFNb effects, as for example MMP-9 concentrations are significantly decreased (as compared to baseline) not before a treatment period of several months [49,85].…”