Quantitative Disease Progression Model of Alpha-1 Proteinase Inhibitor Therapy on CT Lung Density in Patients with Alpha-1 Antitrypsin Deficiency.

Quantitative Disease Progression Model of Alpha-1 Proteinase Inhibitor Therapy on CT Lung Density in Patients with Alpha-1 Antitrypsin Deficiency.

Br J Clin Pharmacol. 2017 Jun 29;:

Authors: Tortorici MA, Rogers JA, Vit O, Bexon M, Sandhaus RA, Burdon J, Chorostowska-Wynimko J, Thompson P, Stocks J, McElvaney NG, Chapman KR, Edelman JM

Abstract
AIMS: Early-onset emphysema attributed to alpha-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human alpha-1 proteinase inhibitor (A1 -PI; 60 mg/kg/wk) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A post-hoc pharmacometric analysis was undertaken to further explore dose, exposure and response.
METHODS: A disease progression model was constructed, utilizing observed A1 -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 A1 -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 A1 -PI, forced expiratory volume in one second and body weight. The exposure-response model relates A1 -PI exposure to lung density decline rate at varying exposure levels.
RESULTS: 60 mg/kg/wk achieved trough serum levels >11 μM (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g/L/yr occurred more often in patients receiving A1 -PI: 63% vs. 12%.
CONCLUSION: Weight-based A1 -PI dosing reliably raises serum levels above the 11 μM threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.

PMID: 28662542 [PubMed - as supplied by publisher]

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