Use of a Highly Purified α1-Antitrypsin Standard to Establish Ranges for the Common Normal and Deficient α1-Antitrypsin Phenotypes

doi:10.1378/chest.100.3.703

Chest

Volume 100, Issue 3, September 1991, Pages 703-708

https://doi.org/10.1378/chest.100.3.703 Get rights and content

Diagnosis of the hereditary disorder α₁-antitrypsin (α₁AT) deficiency is critically dependent on quantification of serum levels of α₁ AT, a 52-kDa antiprotease that serves to protect the lung from destruction by neutrophil elastase. Although the measurement of serum α₁AT levels is not difficult, there is no international standard for α₁AT, and investigators in the field recognize that widely used commercially available standards vary by as much as 50 percent. To establish accurate ranges for the common normal and deficient α₁AT phenotypes, the present study uses a purified α₁AT standard to quantify the α₁AT serum levels of 443 individuals with common normal and deficient α₁ AT phenotypes, including MM, ZZ, SS, MZ, MS, and SZ. Based on the observed values, a statistical model was developed to generate predicted frequency distributions of α₁AT serum levels for each of these phenotypes. Based on these studies, the ranges (5th to 95th percentile) for α₁AT serum levels of the common phenotypes are: MM, 20 to 53 μmol/L; SS, 20 to 48 μmol/L; ZZ, 3.4 to 7.0 μmol/L; MZ, 15 to 42 μmol/L; MS, 18 to 52 μmol/L; and SZ, 10 to 23 μmol/L. This α₁AT standard and these ranges are being used for the National α₁-Antitrypsin Deficiency Registry organized under the auspices of the National Heart, Lung, and Blood Institute. (Chest 1991; 100:703-08)

Section snippets

Study Population

Serum samples were obtained from normal volunteers participating in ongoing studies at the National Institutes of Health (NIH) Clinical Center, from individuals with destructive lung disease associated with α₁AT deficiency and their family members, referred to the Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI). Included in the study population were individuals with the following commomnormal*** and deficient α₁AT phenotypes: MM (n = 197), MZ (n = 56), MS (n = 59), SS (n =

Validation of the Purity and Quantification of the α₁AT Standard

SDS-acrylamide gel electrophoresis of the α₁AT standard demonstrated a single band of 52 kDa, and HPLC analysis demonstrated a single peak of the same molecular weight (Fig 1). These data, together with amino acid analysis generating the expected content of amino acids for the M1(Val²¹³) form of α₁AT (data not shown),¹ confirmed that the purity of the α₁AT preparation was greater than 99 percent. The concentration of the pure α₁AT standard was determined by optical density. This purified α₁AT

ACKNOWLEDGMENTS:

We are indebted to G. Deibler, Laboratory of Cerebral Metabolism, National Institute of Mental Health, for her assistance in amino acid sequence analysis, and J. Travis, Department of Biochemistry, University of Georgia, for independently evaluating the α₁AT standard.

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The recommended standard dose for α₁-proteinase inhibitor (A1PI) augmentation therapy is 60 mg/kg once-weekly (QW) intravenous (IV) infusions that aim to maintain systemic A1PI levels >11 μM, the biochemical efficacy threshold, in patients with α₁-antitrypsin deficiency (AATD). However, this standard dose may not be optimal for all patients. Body weight–based dosing, alternative dosing regimens, and treatment interruption periods were evaluated using population pharmacokinetic (PopPK) modeling and simulations.
A nonlinear mixed-effects PopPK model with covariate effects was developed using data from 3 clinical studies investigating 60 mg/kg QW IV A1PI infusions in patients with AATD (n = 65) to evaluate A1PI pharmacokinetic (PK) characteristics. Model-based simulations were conducted for predefined body weight categories, alternative dosing regimens (60–180 mg/kg QW or once every 2 weeks [Q2W]), and treatment interruption periods ranging from 3 to 14 days.
A1PI PK characteristics were well described by a 2-compartment turnover model with zero-order input and linear elimination. Body weight was a statistically significant determinant of variability in central volume of distribution. Model-based simulations suggested that patients with a higher body weight may attain the 11 μM threshold quicker than patients with a lower body weight and that QW dosing was better at maintaining A1PI levels >11 μM, even when higher Q2W doses were administered. Missing a dose for as few as 3 days could result in A1PI levels <11 μM.
Findings suggest that doses higher than 60 mg/kg administered QW might be more clinically beneficial in some patients with AATD, and that body weight should be considered in dose optimization.
Comparative biochemical efficacy analysis of an alpha<inf>1</inf>-proteinase inhibitor (Glassia®) in patients with alpha-1 antitrypsin deficiency
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Citation Excerpt :
The antigenic A1PI assay methodology using the Behring Nephelometer Analyzer (Behring Diagnostics, Westwood, MA) was validated in plasma and serum samples. The development of the A1PI nephelometry assay has been described previously [21]. The lower limit of quantification was defined as 0.18 μM.
Alpha₁-proteinase inhibitor (A1PI) augmentation is the only specific treatment targeting the underlying deficiency in alpha₁-antitrypsin deficiency (AATD). The demonstration of efficacy has been based on maintaining the biochemical surrogate endpoints of plasma antigenic and functional A1PI levels above >11 μM. Here we report a biochemical comparability analysis based on data from a phase 2/3, randomized, double-blind, two-arm study with partial crossover of Glassia® (Baxalta US Inc. Westlake Village, CA, USA) and Prolastin® (Grifols Therapeutics LLC, Research Triangle Park, NC, USA) in patients with AATD (NCT00460096). Patients (N = 50) were randomly assigned in a 2:1 ratio to receive either Glassia (n = 33) or Prolastin (n = 17), respectively. In the present study, data from patients in the per-protocol population (n = 29, Glassia; n = 12, Prolastin) were analyzed. We compared the biochemical efficacy of these two A1PI products at steady state of A1PI in plasma after weekly intravenous administration of A1PI at a dose of 60 mg/kg body weight. For both antigenic and functional A1PI levels, with or without baseline correction, the geometric mean ratios (GMRs) of plasma trough levels (Glassia/Prolastin) over a 6-week period at steady state (Weeks 7–12 post-randomization) were near or above 100%, with the 90% confidence intervals (CIs) contained within the 80%–125% interval. For antigenic A1PI, the GMR (90% CI) was 115.8% (108.1–124.2) for baseline corrected and 114.2% (109.2–119.5) for uncorrected concentrations. For functional A1PI, the GMR (90% CI) was 98.7 (92.5–105.4) for baseline corrected and 107.8% (102.3–113.5) for uncorrected concentrations. In conclusion, the biochemical efficacy of Glassia using the endpoints of plasma antigenic and functional A1PI trough concentrations at steady state was comparable with Prolastin in patients with AATD.
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Panniculitis represents a rare and potentially lethal manifestation of alpha-1 antitrypsin deficiency (AATD). Evidence regarding management is limited to case reports and small case series. We sought to clarify typical features and investigation of AATD-associated panniculitis and assess the evidence regarding therapeutic options.
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We identified 117 cases of AATD-associated panniculitis. In 1 series, AATD was present in 15% of all cases of biopsy-proven panniculitis. Failure to achieve clinical response was seen in all instances of systemic steroid use. Dapsone, although effective and accessible, is frequently associated with failure to achieve remission. In these instances, intravenous AAT augmentation therapy generally resulted in response.
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Profiling Plasma Extracellular Vesicle-Derived Micrornas for Noninvasive Diagnosis of Liver Disease Associated with Alpha-1 Antitrypsin Deficiency
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Measuring of Alpha-1 Antitrypsin Concentration by Nephelometry or Turbidimetry
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Chest

Clinical InvestigationsUse of a Highly Purified α1-Antitrypsin Standard to Establish Ranges for the Common Normal and Deficient α1-Antitrypsin Phenotypes

Section snippets

Study Population

Validation of the Purity and Quantification of the α1AT Standard

ACKNOWLEDGMENTS:

Chest

Am J Med

Methods Enzymol

J Biochem Biophys Methods

Am J Med

Structure and variation of human α1-antitrypsin.

Nature

α1-Antitrypsin: structure, variation and disease.

Essays Med Biochem

Antielastases of the human alveolar structures: implications for the protease-antiprotease theory of emphysema.

J Clin Invest

Elastases and emphysema: current assessment of the protease-antiprotease hypothesis.

Am Rev Respir Dis

α1-antitrypsin deficiency.

α1-antitrypsin deficiency.

Replacement therapy for alpha1-antitrypsin deficiency associated with emphysema.

N Engl J Med

Efficacy and safety of augmentation therapy of α1-antitrypsin deficiency with monthly infusions of α1-antitrypsin.

JAMA

Report of nomenclature meeting for α1-antitrypsin: INSERM, Rouen/Bois-Guillaume-1978.

Hum Genet

Methoden zur quantitativen bestimmung von plasmaproteinen durch immunprazipitation.

Z Klin Chem Klin Biochem

Isolation and properties of human plasma α1-proteinase inhibitor.

Biochemistry

Properties of isolated human α1-antitrypsins of Pi Types M, S and Z.

Eur J Biochem

Comparison of commercially available radial immunodiffusion kits for the determination of serum α1-antitrypsin concentration.

Am Rev Respir Dis

Clinical Investigations
Use of a Highly Purified α₁-Antitrypsin Standard to Establish Ranges for the Common Normal and Deficient α₁-Antitrypsin Phenotypes

Validation of the Purity and Quantification of the α₁AT Standard

Structure and variation of human α₁-antitrypsin.

α₁-Antitrypsin: structure, variation and disease.

α₁-antitrypsin deficiency.

α₁-antitrypsin deficiency.

Replacement therapy for alpha₁-antitrypsin deficiency associated with emphysema.

Efficacy and safety of augmentation therapy of α₁-antitrypsin deficiency with monthly infusions of α₁-antitrypsin.

Report of nomenclature meeting for α₁-antitrypsin: INSERM, Rouen/Bois-Guillaume-1978.

Isolation and properties of human plasma α₁-proteinase inhibitor.

Properties of isolated human α₁-antitrypsins of Pi Types M, S and Z.

Comparison of commercially available radial immunodiffusion kits for the determination of serum α₁-antitrypsin concentration.