Type

Journal Article

Authors

Jonathan M Edelman
Kenneth R Chapman
Noel G McElvaney
James Stocks
Philip Thompson
Joanna Chorostowska-Wynimko
Jonathan Burdon
Robert A Sandhaus
Martin Bexon
Oliver Vit
and 2 others

Subjects

Medicine & Nursing

Topics
exposure model disease progression computed tomography year 1 clinical trials 1 antitrypsin body weight lung disease

Quantitative disease progression model of α-1 proteinase inhibitor therapy on computed tomography lung density in patients with α-1 antitrypsin deficiency. (2016)

Abstract 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 (A1 -PI; 60 mg kg(-1)  week(-1) ) therapy completed to date, demonstrated for the first time that A1 -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 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 1 s and body weight. The exposure-response model relates A1 -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 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(-1)  year(-1) occurred more often in patients receiving A1 -PI: 63 vs. 12%. Weight-based A1 -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 A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jonathan M Edelman, Kenneth R Chapman, Noel G McElvaney, James Stocks, Philip Thompson, Joanna Chorostowska-Wynimko, Jonathan Burdon, Robert A Sandhaus, Martin Bexon, Oliver Vit and 2 others

Experts in our system

1
Jonathan M Edelman
Royal College of Surgeons in Ireland
Total Publications: 4
 
2
Kenneth R Chapman
Royal College of Surgeons in Ireland
Total Publications: 5
 
3
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
 
4
James M Stocks
Royal College of Surgeons in Ireland
Total Publications: 3
 
5
Robert A Sandhaus
Royal College of Surgeons in Ireland
Total Publications: 4