Summary
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.
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