Bioequivalence of intramuscular and subcutaneous peginterferon beta-1a: results of a phase I, open-label crossover study in healthy volunteers

Abstract

Background: Peginterferon beta-1a administered every 2 weeks via subcutaneous (SC) injection is approved to treat adult patients with relapsing-remitting multiple sclerosis (RRMS) and relapsing forms of multiple sclerosis (RMS). However, associated injection site reactions (ISRs) can lead to treatment discontinuation. Prior studies with interferon beta-1a reported a lower frequency of ISRs with intramuscular (IM) administration than with SC administration. IM administration of peginterferon beta-1a may therefore represent a useful alternative treatment option. Methods: A phase I, open-label, two-period crossover study randomized healthy volunteers to receive a single dose of peginterferon beta-1a 125 mcg administered IM followed by a single 125 mcg dose administered SC after a 28-day washout or vice versa. Blood samples were collected up to 504 h post dose to determine pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The primary endpoint was assessment of bioequivalence based on maximum serum concentration (C max ) and area under the curve from time zero extrapolated to infinity (AUC inf ). Other PK parameters, as well as PD (serum neopterin) and safety profiles, were also evaluated. Results: The study enrolled 136 participants. Bioequivalence of IM and SC peginterferon beta-1a was established for both C max ([least squares (LS)] mean IM/SC ratio: 1.083 [90% confidence interval (CI), 0.975–1.203]) and AUC inf (LS mean IM/SC ratio: 1.089 [90% CI, 1.020–1.162]). Other PK and PD parameters were similar between administration routes, although moderate to high inter-subject variability was observed for IM and SC. Safety profiles were generally balanced between IM and SC administration. ISRs occurred at a lower frequency with IM [14.4% (95% CI, 8.89–21.56%)] than with SC [32.1% (95% CI, 24.29–40.70%)] administration ( p = 0.0005). Conclusions: These results demonstrate bioequivalence between peginterferon beta-1a IM and SC and support the consideration of IM injection of peginterferon beta-1a as a viable treatment option in patients with RRMS and RMS.