Michael A. Tortorici , 1 , James A. Rogers 2 , Oliver Vit 3 , Martin Bexon 3 , Robert A. Sandhaus 4 , Jonathan Burdon 5 , Joanna Chorostowska‐Wynimko 6 , Philip Thompson 7 , James Stocks 8 , Noel G. McElvaney 9 , Kenneth R. Chapman 10 , Jonathan M. Edelman 1
11 August 2017
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.