Bioequivalence of a Liquid Formulation of Alpha1-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha1-PI) in Alpha1-Antitrypsin Deficiency

Abstract

This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha₁-proteinase inhibitor, Liquid Alpha₁-PI, compared with the Lyophilized Alpha₁-PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha₁-antitrypsin deficiency (AATD). In this double-blind, randomized, 20-week crossover study, 32 subjects with AATD were randomized to receive 8 weekly infusions of 60 mg/kg of Liquid Alpha₁-PI or Lyophilized Alpha₁-PI. Serial blood samples were drawn for 7 days after the last dose followed by 8 weeks of the alternative treatment. The primary endpoint was bioequivalence at steady state, as measured by area under the concentration versus time curve from 0 to 7 days (AUC_{0-7 days}) postdose using an antigenic content assay. Bioequivalence was defined as 90% confidence interval (CI) for the ratio of the geometric least squares (LS) mean of AUC_{0-7 days} for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha₁-PI concentration versus time curves for both formulations were superimposable. Mean AUC_{0-7 days} was 20 320 versus 19 838 mg × h/dl for Liquid Alpha₁-PI and Lyophilized Alpha₁-PI, respectively. The LS mean ratio of AUC_{0-7 days} (90% CI) for Liquid Alpha₁-PI versus Lyophilized Alpha₁-PI was 1.05 (1.03-1.08), indicating bioequivalence. Liquid Alpha₁-PI was well tolerated and adverse events were consistent with Lyophilized Alpha₁-PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha₁-PI is bioequivalent to Lyophilized Alpha₁-PI, with a similar safety profile. The liquid formulation would eliminate the need for reconstitution and shorten preparation time for patients receiving augmentation therapy for AATD.

Keywords: Antigenic content assay; augmentation therapy; clinical trial; functional activity assay; pharmacokinetics.