Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha₁-antitrypsin deficiency: a randomized study

James M Stocks, Mark L Brantly, Laurene Wang-Smith, Michael A Campos, Kenneth R Chapman, Friedrich Kueppers, Robert A Sandhaus, Charlie Strange, Gerard Turino, James M Stocks, Mark L Brantly, Laurene Wang-Smith, Michael A Campos, Kenneth R Chapman, Friedrich Kueppers, Robert A Sandhaus, Charlie Strange, Gerard Turino

Abstract

Background: Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha₁-PI) and may lead to emphysema. Alpha₁-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha₁-Proteinase Inhibitor [Human]) to increase the levels of alpha₁-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha₁-PI product, designated Prolastin®-C (Alpha₁-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency.

Methods: In total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC₀₋₇ (days)) of alpha₁-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only.

Results: Mean AUC₀₋₇ (days) was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC₀₋₇ (days) for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study.

Conclusion: Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin.

Trial registration: ClinicalTrials.gov Identifier: NCT00295061.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Subject disposition.
Figure 3
Figure 3
Mean plasma alpha1-PI concentration versus time curves following treatment with Prolastin-C or Prolastin: potency [functional activity] assay results.
Figure 4
Figure 4
Mean plasma alpha1-PI concentration versus time curves following treatment with Prolastin-C or Prolastin: content [antigenic] assay results.

References

    1. de Serres FJ. Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed. Environ Health Perspect. 2003;111:1851–1854. doi: 10.1289/ehp.6511.
    1. Kohnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. Am J Med. 2008;121:3–9. doi: 10.1016/j.amjmed.2007.07.025.
    1. Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008;3:16–24. doi: 10.1186/1750-1172-3-16.
    1. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168:818–900. doi: 10.1164/rccm.168.7.818.
    1. The Alpha-1-Antitrypsin Deficiency Registry Study Group: Survival and FEV1 decline in individuals with severe deficiency of alpha 1-antitrypsin. Am J Respir Crit Care Med. 1998;158:49–59.
    1. Wencker M, Fuhrmann B, Banik N, Konietzko N. Longitudinal follow-up of patients with α1-protease inhibitor deficiency before and during therapy with IV α1-protease inhibitor. Chest. 2001;119:737–744. doi: 10.1378/chest.119.3.737.
    1. Chapman KR, Stockley RA, Dawkins C, Wilkes MM, Navickis RJ. Augmentation therapy for alpha 1 antitrypsin deficiency: a meta-analysis. COPD. 2009;6:177–184. doi: 10.1080/15412550902905961.
    1. Wencker M, Banik N, Buhl R, Seidel R, Konietzko N. Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-AT-study group. Eur Respir J. 1998;11:428–433. doi: 10.1183/09031936.98.11020428.
    1. Stoller JK, Fallat R, Schluchter MD, O'Brien RG, Connor JT, Gross N, O'Neil K, Sandhaus R, Crystal RG. Augmentation therapy with alpha1-antitrypsin: patterns of use and adverse events. Chest. 2003;123:1425–1434. doi: 10.1378/chest.123.5.1425.
    1. Bernhardt T, Cortes R. Post license safety of prolastin. Eur Respir J. 2006;28(Suppl 50):518s.
    1. Pifat D, Osheroff W, Hotta J, Roth N, Cai K, Petteway S. Pathogen safety of Prolastin®. Eur Respir J. 2006;28(Suppl 50):518s.
    1. Burdick MD, Pifat DY, Petteway SR, Cai K. Clearance of prions during plasma protein manufacture. Transfus Med Rev. 2006;20:57–62. doi: 10.1016/j.tmrv.2005.08.005.
    1. Zimmerman TP. Yield improvement for manufacture of alpha-proteinase inhibitor. Vox Sang. 2006;91:309–315. doi: 10.1111/j.1423-0410.2006.00841.x.
    1. Cai K, Gierman TM, Hotta J, Stenland CJ, Lee DC, Pifat DY, Petteway SR Jr. Ensuring the biologic safety of plasma-derived therapeutic proteins: detection, inactivation, and removal of pathogens. BioDrugs. 2005;19:79–96. doi: 10.2165/00063030-200519020-00002.
    1. Beatty K, Bieth J, Travis J. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem. 1980;255:3931–3934.
    1. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence; 2001. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER) Accessed May 2010.

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