In:
British Journal of Clinical Pharmacology, Wiley, Vol. 83, No. 11 ( 2017-11), p. 2386-2397
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 (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. Methods 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. 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 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%. Conclusion 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.
Type of Medium:
Online Resource
ISSN:
0306-5251
,
1365-2125
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
1498142-7
SSG:
15,3
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