Impaired Bioavailability of Interferon Beta-1a when Administered Intramuscularly by Needle-Free Injection

Abstract

Intramuscular (IM) or subcutaneous (SC) drug administration of small molecules and protein has been demonstrated by use of needle-free jet injection methods. One device that achieves needle-free parenteral administration, BIOJECTORr`, is commercially available and was evaluated for IM delivery of interferon beta-1a. Recombinant human interferon beta-1a (IFN β-1a) is a glycosylated protein containing 166 amino acids and has a molecular weight of 22.5 kDa. Needle-free jet injection of IFN β-1a with the BIOJECTORr` was assessed in a human Phase I trial. The study was a randomized, open-label crossover in which 12 healthy subjects each received 60 μ of IFN β-1a as an IM injection by standard needle administration and by needle-free jet injection. Blood samples for pharmacokinetic (serum activity, PK) and pharmacodynamic (serum neopterin, PD) determinations were collected through 144 hours post-dose. Mean serum antiviral activity AUC values for needle-free and standard needle injection were 218 and 531 U x h/ml, respectively; corresponding C^max values were 19.7 and 29.0 U/ml. Median T_max following both treatments was 12 hours. The relative bioavailability of IFN β-1a, needle-free to standard needle injection, was 41.1% with 90% confidence limits of 24.4% to 69.3%. Mean serum neopterin EAUC values for needle-free and standard needle injection were 114 and 325 ng x h/mL, respectively; corresponding E_max values were 2.3 and 5.6 ng/mL. The ratio of serum neopterin E_AUC, needle-free to standard needle, was 34.9% with 90% confidence limits of 23.4% to 52.1%. Injection site reactions were substantially more frequent following needle-free injection; however, systemic side effects were less frequent. Intramuscular needle-free jet injection and needle-based injection of a 22.5-kDa glycoprotein do not produce equivalent systemic PK or PD responses.

Key Words:

• Pharmacokinetics
• Pharmacodynamics
• Interferon Beta-1a
• Needle-free Injection