title: 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).
abstract: Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 μM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-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 alpha1-PI (Prolastin-C®) 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 AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-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 alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-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.
authors.affiliation: 1University of Miami School of Medicine , Miami, Florida , USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Campos
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kueppers
authors.forename: James M
authors.initials: JM
authors.lastname: Stocks
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.forename: Junliang
authors.initials: J
authors.lastname: Chen
authors.forename: Rhonda
authors.initials: R
authors.lastname: Griffin
authors.forename: Laurene
authors.initials: L
authors.lastname: Wang-Smith
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015331:Cohort Studies; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D015842:Serine Proteinase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin