TY - JOUR
T1 - Quantitative disease progression model of α-1 proteinase inhibitor therapy on computed tomography lung density in patients with α-1 antitrypsin deficiency
AU - Tortorici, Michael A.
AU - Rogers, James A.
AU - Vit, Oliver
AU - Bexon, Martin
AU - Sandhaus, Robert A.
AU - Burdon, Jonathan
AU - Chorostowska-Wynimko, Joanna
AU - Thompson, Philip
AU - Stocks, James
AU - McElvaney, Noel G.
AU - Chapman, Kenneth R.
AU - Edelman, Jonathan M.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Aims: 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. 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 1 s and body weight. The exposure–response model relates A1-PI exposure to lung density decline rate at varying exposure levels. Results: 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%. Conclusion: 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.
AB - Aims: 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. 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 1 s and body weight. The exposure–response model relates A1-PI exposure to lung density decline rate at varying exposure levels. Results: 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%. Conclusion: 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.
KW - chronic obstructive pulmonary disease
KW - imaging
KW - modelling and simulation
UR - http://www.scopus.com/inward/record.url?scp=85031920165&partnerID=8YFLogxK
U2 - 10.1111/bcp.13358
DO - 10.1111/bcp.13358
M3 - Article
C2 - 28662542
AN - SCOPUS:85031920165
VL - 83
SP - 2386
EP - 2397
JO - British Journal Clinical Pharmacology
JF - British Journal Clinical Pharmacology
SN - 0306-5251
IS - 11
ER -