Assessment of the safety, tolerability, and PK/PD properties of two new formulations of subcutaneously administered IFN-beta1a: a double-blind, placebo-controlled comparison with the currently available formulation.

OBJECTIVE: Application-site disorders are well-known adverse events (AEs) associated with subcutaneous (s.c.) injection. With high-dose, high-frequency interferon (IFN)-beta1a (Rebif) these AEs are generally mild but may lead to the discontinuation of some patients. The objective of this study was to compare the safety, tolerability, and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of two new formulations of Rebif (Rebif New Formulation: RNF1 and RNF2) with the current formulation (hereafter referred to as R) and placebo. METHODS: In this double-blind, placebo-controlled, parallel-group, Phase I study, healthy volunteers of both sexes were randomized 1:1:1:1 to receive a single 0.5 ml s.c. dose of RNF1, RNF2, R or placebo (normal saline). The three active treatments contained 44 microg IFN-beta1a. During the 24-hour post-dose period, safety and tolerability assessments were conducted and blood samples were taken at regular intervals for PK and PD analyses. Pain intensity on injection was measured using the short-form McGill questionnaire and a 100 mm visual analogue scale (VAS). Further safety assessments were performed and blood samples taken at 24-hour intervals until Day 7 post-dose, with a final post-study visit 10- 14 days after dosing. RESULTS: A total of 48 subjects (22 men, 26 women) were recruited and allocated equally to each treatment (12 subjects per group). AEs were reported by 10 subjects in each active treatment group and by 3 subjects in the placebo group. All AEs were consistent with the known safety profile of R. The number of treatment-emergent AEs was lower in the RNF2 group than the RNF 1 or R groups (21, 31 and 33 events, respectively). Redness at the injection site was mostly mild and occurred in fewer subjects in the RNF2 group (n = 3) than the RNF 1 or R groups (n = 7 and n = 4, respectively). Injection site pain was reported by 1 subject in the RNF2 group, compared with 4, 6 and 3 subjects, respectively, in the RNF1, R and placebo groups. The worst pain intensity, as measured by VAS, was lower in the RNF2 and RNFI groups than either the R or placebo groups. There was considerable intersubject variability in the PK and PD profiles of the three formulations of IFN-beta1a. Nevertheless, the PK and PD characteristics of RNF2 were similar to those of R. CONCLUSIONS: The results from this study suggest that RNF2 may offer improved tolerability compared with the current formulation of R, but retains comparable pharmacokinetic and pharmacodynamic characteristics.