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

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.