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

Abstract

AimsEarly‐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.MethodsA 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.ResultsA 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%.ConclusionWeight‐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.

Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know

“…Whether the standard recommended dose of 60 mg/kg is most adequate remains unclear, as some patients on the standard dose can still exhibit residual inflammation, protease activity, and elastin degradation which can be further mitigated by increasing the treatment dose. 78 Pharmacometric analysis of data from the RAPID trials has suggested that increasing serum levels above the 11 µM threshold is associated with greater clinical effect; 56,104 a finding that was supported by a recent pilot study, which observed significant improvements in multiple markers of disease activity in patients up-titrated from 60 to 120 mg/kg AAT per week. 78 Increasing the dose to 120 mg/kg per week was also well tolerated and restored serum AAT levels to be more in line with the normal range (>25 µM).…”

Updates in the Management of Alpha-1 Antitrypsin Deficiency Lung Disease

“…27 Tortorici et al, who found that clinical efficacy did not plateau as AAT exposure was increased, suggested that there may be a role for higher AAT doses. 28 The SPARK trial (Safety and Pharmacokinetics of Alpha-1 Proteinase Inhibitor in Subjects with Alpha-1 Antitrypsin Deficiency; ClinicalTrials identifier: NCT01213043) in 2013 found that double-dose 120 mg/kg/week achieved a higher mean steady state serum concentration of 27.7 µM (versus 17.3 µM in the 60 mg/kg/week group) with a similar safety profile. 29 A follow-up pilot study with eight patients with AATD was conducted in 2019, which found that double-dose therapy for 4 weeks significantly reduced serine protease activity in bronchoalveolar lavage fluid (BALF) and plasma, and reduced markers of elastin degradation (desmosine, isodesmosine) in BALF.…”

Focussing on The Patient: Future Prospects in Alpha 1 Management

“…Data from population pharmacokinetic simulations predicted that trough levels above the 11 µM protective threshold would be maintained in the majority of patients treated with bi-weekly 120 mg/kg infusions. 30,31 (CSL Behring, data on file). Furthermore, a pharmacokinetic model suggested a linear relationship between AAT dose and AAT serum levels within the concentrations investigated.…”