Safety of bi-weekly infusion of A<sub>1</sub>-PI augmentation therapy in RAPID

Seersholm, Niels; Sandhaus, Robert A.; Burdon, Jonathan; Piitulainen, Eeva; Stocks, James M.; Tortorici, Michael A.; Rosenberg, Tanja; Vit, Oliver; Bexon, Martin; Edelman, Jonathan M.; McElvaney, N.G.

doi:10.1183/13993003.congress-2015.pa999

Cited by 8 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinical trials aimed at investigating the efficacy of AAT supplementation reported a beneficial effect of this treatment in terms of change of pulmonary density, decreased number of exacerbations/year and improved survival [ 87 , 88 ]. Several trials reported increased serum levels and anti-elastase capacity of these treatments in patients with AATD, confirming the stability of AAT serum levels in patients treated with intravascular AAT supplementation without serious adverse effects along with a positive effect of supplementation therapy on clinical endpoints as lung function decline, exacerbations risk and mortality [ 82 , 88 ]. All treatments listed in Table 1 represent different formulation of AAT augmentation therapy developed and available on the market.…”

Section: Treatments Of Protease–antiprotease Imbalance In Bronchiectasismentioning

confidence: 87%

Protease–Antiprotease Imbalance in Bronchiectasis

Oriano

Amati

Gramegna

et al. 2021

IJMS

View full text Add to dashboard Cite

Airway inflammation plays a central role in bronchiectasis. Protease–antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases’ over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease–antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.

show abstract

Section: Treatments Of Protease–antiprotease Imbalance In Bronchiectasismentioning

confidence: 87%

Protease–Antiprotease Imbalance in Bronchiectasis

Oriano

Amati

Gramegna

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Therefore, a linear relationship between dose and exposure (with no clear evidence of a plateau at any serum concentration) is expected. The safety of higher doses, however, is not evaluable from the present analysis and, as previously discussed, the long-term evidence for the safety of higher A 1 -PI doses, although supportive, remains limited [12,15,18,24,25].…”

Section: Model Validity and Limitationsmentioning

confidence: 60%

“…Double (120 mg kg –1 ) weekly doses of A 1 ‐PI have previously been shown to be well tolerated and can increase serum levels further than the standard 60 mg kg –1 dose . Furthermore, in RAPID‐RCT, 333 doses of 120 mg kg –1 A 1 ‐PI were administered to cover 2‐week periods, with no relevant increase in treatment‐related adverse events observed . However, the long‐term safety and efficacy of A 1 ‐PI therapy at 120 mg kg –1 and above has yet to be proven; data are awaited from studies incorporating 120 mg kg –1 dosing .…”

Section: Discussionmentioning

confidence: 99%

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

Tortorici

Rogers

Vit

et al. 2017

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…The 120 mg/kg bi-weekly dose achieved serum levels above the 11 µM protective threshold and was well tolerated, causing no serious adverse events. 82 In addition, regimens of 100/120 mg/kg every 2 weeks, 150/180 mg/kg every 3 weeks and 250 mg/kg every 4 weeks have also been studied in pharmacokinetic simulations to estimate the individual optimal dose for AAT replacement therapy. While infusions of 100/120 mg/kg every 2 weeks can sustain serum AAT levels above the protective threshold, 83 longer infusion intervals, such as monthly infusions of 250 mg/kg, failed to maintain the protective serum concentrations across the full 28 days of the dose window.…”

Section: Discussionmentioning

confidence: 99%

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications

Chorostowska‐Wynimko¹,

Koczulla²,

Ferrarotti

et al. 2018

COPD

View full text Add to dashboard Cite

Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency.

show abstract

Safety of bi-weekly infusion of A₁-PI augmentation therapy in RAPID

Cited by 8 publications

References 0 publications

Protease–Antiprotease Imbalance in Bronchiectasis

Protease–Antiprotease Imbalance in Bronchiectasis

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

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications

Contact Info

Product

Resources

About

Safety of bi-weekly infusion of A1-PI augmentation therapy in RAPID

Cited by 8 publications

References 0 publications

Protease–Antiprotease Imbalance in Bronchiectasis

Protease–Antiprotease Imbalance in Bronchiectasis

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

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications

Contact Info

Product

Resources

About

Safety of bi-weekly infusion of A₁-PI augmentation therapy in RAPID