Safety and Pharmacokinetics of 120 mg/kg versus 60 mg/kg Weekly Intravenous Infusions of Alpha-1 Proteinase Inhibitor in Alpha-1 Antitrypsin Deficiency: A Multicenter, Randomized, Double-Blind, Crossover Study (SPARK)

Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha(1)-PI), achieves a trough serum level of 11 mu M in individuals with alpha-1 antitrypsin defi ciency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profi le of weekly infusions of a 120 mg/kg dose of alpha(1)-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z) Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha(1)-PI (Prolastin-C (R)) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC(0-7days), C-max,C- trough, t(max), and t1/2, based on serum alpha(1)-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha(1)-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 mu M, respectively. Dose proportionality was demonstrated for AUC(0-7days) and C-max, with low inter-subject variability. The 120 mg/kg alpha(1)-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha(1)-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.