Dataset Information

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

ABSTRACT:

Aims

Early-onset emphysema attributed to ?-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human ?-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 ?mol 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 ?mol 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.

SUBMITTER: Tortorici MA

PROVIDER: S-EPMC5651313 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Tortorici Michael A MA Rogers James A JA Vit Oliver O Bexon Martin M Sandhaus Robert A RA Burdon Jonathan J Chorostowska-Wynimko Joanna J Thompson Philip P Stocks James J McElvaney Noel G NG Chapman Kenneth R KR Edelman Jonathan M JM

British journal of clinical pharmacology 20170811 11

<h4>Aims</h4>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<sub>1</sub> -PI; 60 mg kg<sup>-1</sup> week<sup>-1</sup> ) therapy completed to date, demonstrated for the first time that A<sub>1</sub> -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, ex ...[more]

PMID: 28662542

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