Pharmacokinetics and Biochemical Efficacy of an α1-Proteinase Inhibitor (Aralast NP) in α1-Antitrypsin Deficiency: a Cross-Product Retrospective Comparability Analysis

Abstract

Introduction: Augmentation therapy with plasma-derived α1-proteinase inhibitor (A1PI) products is currently the only approved disease-specific therapy for α1-antitrypsin deficiency (AATD), a genetic disorder associated with decreased levels of A1PI. Systemic trough levels of A1PI in plasma or serum are widely accepted as a biochemical efficacy endpoint in clinical trials for A1PI products.

Methods: Retrospective analyses utilizing data from three clinical studies in patients with AATD were conducted to evaluate the pharmacokinetic(s) (PK) and biochemical efficacy comparability of Aralast NP and two other A1PI augmentation therapies, Aralast and Prolastin. All three A1PI products were administered as either single or multiple 60 mg/kg intravenous infusions. PK and biochemical efficacy comparability analyses were conducted by evaluating antigenic and functional A1PI serum or plasma concentration data from each of the three studies.

Results: Comparable PK parameters were demonstrated between the three products for antigenic A1PI levels following a single infusion, with baseline-corrected and uncorrected geometric mean ratios for peak and systemic exposure ranging from 89.0% to 99.6%, with 90% confidence intervals within the 80-125% reference interval for bioequivalence. Biochemical efficacy comparability analyses of Aralast and Prolastin after multiple infusions at steady state showed geometric mean ratios for uncorrected and baseline-corrected antigenic and functional A1PI trough concentrations over weeks 8-11, and for individual weeks, that ranged from 75.8% to 106.6%, with the majority of the 90% confidence intervals falling either within the 80-125% interval or in proximity to it. Nonparametric superpositioning at steady state suggested that predicted trough concentrations for Aralast NP were comparable to the observed concentrations for Aralast and Prolastin.

Conclusion: These retrospective analyses provide robust evidence that Aralast NP has biochemical efficacy and PK comparable to that of Aralast and Prolastin, supporting the use of any of these A1PI products for the treatment of patients with AATD.

Trial registration numbers: ClinicalTrials.gov identifiers, NCT00242385 and NCT00396006.

Keywords: Biochemical efficacy; Pharmacokinetic comparability; α1-antitrypsin deficiency; α1-proteinase inhibitor.

© 2022. The Author(s).

Figures

Fig. 1

Study design schematics for a study 1, b study 2, and c study 3. aAll samples were taken immediately prior to infusion and represented the trough level of the previous week’s infusion. bThe eight consecutive weekly doses of Aralast NP were to be administered without interruption and without chronic obstructive pulmonary disease exacerbation or LRTI. If treatments were missed, the count restarted. If a moderate or severe acute pulmonary exacerbation or LRTI occurred, the count restarted 2 weeks after either the pulmonary exacerbation or LRTI was no longer evident. BAL bronchoalveolar lavage, IV intravenous, LRTI lower respiratory tract infection, PK pharmacokinetic

Fig. 2

Study 1 mean ± SD a baseline-corrected and b uncorrected antigenic A1PI serum concentration–time profiles after a single IV infusion. Baseline-corrected values were calculated by subtracting baseline (pre-infusion) concentrations from subsequent concentration–time values. A1PI α1-proteinase inhibitor, IV intravenous, SD standard deviation

Fig. 3

Study 2 mean ± SD a baseline-corrected and b uncorrected antigenic A1PI plasma concentration–time profiles after a single IV infusion. Baseline-corrected values were calculated by subtracting baseline (pre-infusion) concentrations from subsequent concentration–time values. A1PI α1-proteinase inhibitor, IV intravenous, SD standard deviation

Fig. 4

Study 1 mean ± SD baseline-corrected and uncorrected a antigenic and b functional A1PI serum concentration–time profiles after multiple IV infusions. Baseline-corrected values were calculated by subtracting baseline (week 1 pre-dose trough level) concentrations of antigenic or functional A1PI from subsequent trough concentrations. A1PI α1-proteinase inhibitor, IV intravenous, SD standard deviation. The uncorrected antigenic A1PI serum concentration–time profile presented in a has been adapted from Chest, Vol 122, Issue 1. Stoller JK et al. Biochemical efficacy and safety of a new pooled human plasma α1-antitrypsin, Respitin, pages 66–74, Copyright © 2002 with permission from Elsevier on behalf of The American College of Chest Physicians

Fig. 5

a Linear-scale and b log-scale predicted concentration–time profiles for patients receiving Aralast NP compared with observed mean ± SD baseline-corrected antigenic A1PI trough concentrations after multiple IV infusions. Baseline-corrected values were calculated by subtracting baseline (week 1 pre-dose trough level) concentrations of antigenic A1PI from subsequent trough concentrations. A1PI α1-proteinase inhibitor, CI confidence interval, IV intravenous, NPS nonparametric superpositioning, SD standard deviation