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      Quantitative disease progression model of α‐1 proteinase inhibitor therapy on computed tomography lung density in patients with α‐1 antitrypsin deficiency

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          Early‐onset emphysema attributed to α‐1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID‐RCT/RAPID‐OLE, the largest clinical trials of purified human α‐1 proteinase inhibitor (A 1‐PI; 60 mg kg –1 week –1) therapy completed to date, demonstrated for the first time that A 1‐PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.


          A disease progression model was constructed, utilizing observed A 1‐PI exposure and lung density decline rates (measured by computed tomography) from RAPID‐RCT/RAPID‐OLE, to predict effects of population variability and higher doses on A 1‐PI exposure and clinical response. Dose–exposure and exposure–response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose–exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A 1‐PI, forced expiratory volume in 1 s and body weight. The exposure–response model relates A 1‐PI exposure to lung density decline rate at varying exposure levels.


          A dose of 60 mg kg –1 week –1 achieved trough serum levels >11 μmol l –1 (putative ‘protective threshold’) in ≥98% patients. Dose–exposure–response simulations revealed increasing separation between A 1‐PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l –1 year –1 occurred more often in patients receiving A 1‐PI: 63 vs. 12%.


          Weight‐based A 1‐PI dosing reliably raises serum levels above the 11 μmol l –1 threshold. However, our exposure–response simulations question whether this is the maximal, clinically effective threshold for A 1‐PI therapy in AATD. The model suggested higher doses of A 1‐PI would yield greater clinical effects.

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          Most cited references 17

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          Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

          The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure.
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            Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency.

            Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation.
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              A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy.

              We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr.

                Author and article information

                Br J Clin Pharmacol
                Br J Clin Pharmacol
                British Journal of Clinical Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                11 August 2017
                November 2017
                11 August 2017
                : 83
                : 11 ( doiID: 10.1111/bcp.v83.11 )
                : 2386-2397
                [ 1 ] Clinical Strategy and Development CSL Behring King of Prussia Pennsylvania USA
                [ 2 ] Metrum Research Group LLC Tariffville Connecticut USA
                [ 3 ] Global Clinical Research and Development CSL Behring Bern Switzerland
                [ 4 ] Division of Pulmonary, Critical Care and Sleep Medicine National Jewish Health Denver Colorado USA
                [ 5 ] Respiratory Medicine St. Vincent's Hospital Melbourne V ictoria Australia
                [ 6 ] Department of Genetics and Clinical Immunology National Institute of Tuberculosis and Lung Diseases Warsaw Poland
                [ 7 ] Molecular Genetics and Inflammation Unit, Institute of Respiratory Health and School of Medicine University of Western Australia, Perth Western Australia Australia
                [ 8 ] Pulmonary and Critical Care University of Texas Health Science Center at Tyler Tyler Texas USA
                [ 9 ] Department of Respiratory Medicine Beaumont Hospital, Royal College of Surgeons in Ireland Dublin Ireland
                [ 10 ] Department of Medicine University of Toronto Toronto Ontario Canada
                Author notes
                [* ] Correspondence

                Michael A. Tortorici, PharmD, PhD, Clinical Strategy and Development, CSL Behring, King of Prussia, Pennsylvania, 19406 USA. Tel.: +1 610 878 4587; Fax: +1 610 290 9587; E‐mail: michael.tortorici@

                BCP13358 MP-00892-16.R2
                © 2017 CSL Behring. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 6, Tables: 3, Pages: 12, Words: 6499
                Funded by: CSL Behring
                Funded by: CSL Behring
                Custom metadata
                November 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:23.10.2017


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