A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD
Abstract:BackgroundFunctional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance.Patients and methodsIn this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 μg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the followin… Show more
“…In the GFF MDI study, there were large improvements in siVaw (75% increase) and siRaw (71% decrease) versus placebo MDI at Day 15 with the effects observed across all lobes of the lung ( Figure 3A , 4A and B ). 56 These changes were accompanied by clinically meaningful improvements in spirometry and body plethysmography endpoints, with differences for GFF MDI versus placebo of 443 mL and 454 mL for FEV 1 and IC ( Figure 3B ), and 13% and 22% reductions versus placebo for functional residual capacity and residual volume. At the patient level, improvements in FRI parameters were strongly correlated with the change from baseline in FEV 1 , supporting the validity of this image-based technique to assess bronchodilator medications in respiratory disease, with the added benefit of providing information regarding the regional distribution of the observed effects.…”
Section: Attributes Of Co-suspension Delivery Technologymentioning
confidence: 88%
“… Optimal particle size enables delivery to the large and small airways 12 , 20 , 46 Treatment benefits are observed throughout the lung. 56 Abbreviations: MDI, metered dose inhaler; MMAD, mass median aerodynamic diameter. Figure 1 Overview of co-suspension delivery technology, as used in the Aerosphere inhaler.…”
Section: What Is Co-suspension Delivery Technology?mentioning
confidence: 99%
“…Two FRI studies of MDIs formulated using co-suspension delivery technology have been conducted in patients with moderate-to-severe COPD. 56 , 61 The first of these studies compared GFF MDI with placebo MDI, 56 whereas the second evaluated the monocomponents of GFF MDI: GP MDI and FF MDI. 61 Both studies used a crossover design with two 14-day treatment periods, separated by a washout period of 5 to 21 days.…”
Section: Attributes Of Co-suspension Delivery Technologymentioning
Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug-drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The Aerosphere TM inhaler, formulated using cosuspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.
“…In the GFF MDI study, there were large improvements in siVaw (75% increase) and siRaw (71% decrease) versus placebo MDI at Day 15 with the effects observed across all lobes of the lung ( Figure 3A , 4A and B ). 56 These changes were accompanied by clinically meaningful improvements in spirometry and body plethysmography endpoints, with differences for GFF MDI versus placebo of 443 mL and 454 mL for FEV 1 and IC ( Figure 3B ), and 13% and 22% reductions versus placebo for functional residual capacity and residual volume. At the patient level, improvements in FRI parameters were strongly correlated with the change from baseline in FEV 1 , supporting the validity of this image-based technique to assess bronchodilator medications in respiratory disease, with the added benefit of providing information regarding the regional distribution of the observed effects.…”
Section: Attributes Of Co-suspension Delivery Technologymentioning
confidence: 88%
“… Optimal particle size enables delivery to the large and small airways 12 , 20 , 46 Treatment benefits are observed throughout the lung. 56 Abbreviations: MDI, metered dose inhaler; MMAD, mass median aerodynamic diameter. Figure 1 Overview of co-suspension delivery technology, as used in the Aerosphere inhaler.…”
Section: What Is Co-suspension Delivery Technology?mentioning
confidence: 99%
“…Two FRI studies of MDIs formulated using co-suspension delivery technology have been conducted in patients with moderate-to-severe COPD. 56 , 61 The first of these studies compared GFF MDI with placebo MDI, 56 whereas the second evaluated the monocomponents of GFF MDI: GP MDI and FF MDI. 61 Both studies used a crossover design with two 14-day treatment periods, separated by a washout period of 5 to 21 days.…”
Section: Attributes Of Co-suspension Delivery Technologymentioning
Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug-drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The Aerosphere TM inhaler, formulated using cosuspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.
“…Pressures and velocities through the airway tree were determined by numerically solving the Navier Stokes equations. The approach has been validated using SPECT CT scans, and by correlating changes in FRI-based resistance with changes in FEV 1 after administration of a bronchodilator in asthma and COPD [18][19][20][21].…”
Background: The mechanism for symptomatic improvement after bronchial thermoplasty (BT) is unclear, since spirometry reveals little or no change. In this study, the effects of BT on airway resistance were examined using two independent techniques. Methods: Eighteen consecutive patients, with severe asthma (57.6 ± 14.2 years) were evaluated by spirometry and plethysmography at three time points: (i) baseline, (ii) left lung treated but right lung untreated and (iii) 6 weeks after both lungs were treated with BT. At each assessment, total and specific airway resistance (Raw, sRaw) were measured. High resolution CT scans were undertaken at the first two assessments, and measurements of lobar volume, airway volume and airway resistance were made. The Asthma Control Questionnaire (ACQ) was administered at each assessment. Results: The baseline ACQ score was 3.5 ± 0.9, and improved progressively to 1.8 ± 1.2 (p < 0.01). At baseline, severe airflow obstruction was observed, FEV1 44.8 ± 13.7% predicted, together with gas trapping, and elevated Raw at 342 ± 173%predicted. Following BT, significant improvements in Raw and sRaw were observed, as well as a reduction in Residual Volume, increase in Vital Capacity and no change in FEV1. The change in Raw correlated with the change in ACQ (r = 0.56, p < 0.05). CT scans demonstrated reduced airway volume at baseline, which correlated with the increased Raw determined by plethysmography (p = − 0.536, p = < 0.05). Following BT, the airway volume increased in the treated lung, and this was accompanied by a significant reduction in CT-determined local airway resistance. Conclusion: Symptomatic improvement after BT is mediated by increased airway volume and reduced airway resistance.
“…The authors, observing the small sample size, exercised caution in those patients with a qCT-predicted FEV 1 <40% who have a higher risk of post-operative morbidity and mortality, and advised the addition of perfusion scintigraphy and exercise testing for comprehensive evaluation. Functional respiratory imaging, combining high-resolution CT and post-processing computational fluid dynamics, can be used to assess airway volume and resistance at a lobar level and is more sensitive to pharmacologically induced changes than routine lung function tests [ 16 ]. Total lung capacity and residual volumes, estimated on CT scans respectively made in maximum inspiration and expiration have also been shown to correlate well with plethysmography derived measurements ( figure 1 ) [ 17 ].…”
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