The Effects of Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, Hyperinflation, and Airway Geometry in COPD Patients: Novel Insight Using Functional Respiratory Imaging

Abstract

Background: The efficacy of inhaled corticosteroids (ICS) in moderately severe COPD patients remains unclear. At the same time, the use of extrafine particles in COPD patients is a topic of ongoing research. Objectives: This study assessed the effect of ICS in steroid-naïve mild COPD patients and the effect of reducing the ICS dose in more severe COPD patients previously using ICS when switching to an extrafine particle BDP/F formulation (Foster using Modulite technology, Chiesi Pharmaceutici, Parma, Italy). Methods: Novel functional respiratory imaging (FRI) methods, consisting of multi-slice CT scans and Computational Fluid Dynamics, were used in combination with conventional pulmonary function tests and patient reported outcomes. Results: The study showed that the administration of extrafine BDP/F after 4-6 h led to a significant improvement in lung function parameters and hyperinflation as determined by spirometry, body plethysmography, and functional respiratory imaging. After 6 months of treatment, it was observed that, compared to baseline, the hyperinflation on lobar level at total lung capacity was significantly reduced (-1.19 -7.19 %p, p¼0.009). In addition, a significant improvement in SGRQ symptom score was noted in the entire patient population. Patients who improved in terms of hyperinflation also improved their MMRC dyspnea score. CFD indicated a difference in regional deposition between extrafine and non-extrafine formulations with -11% extrathoracic deposition and up to + 4% lobe deposition for the extrafine formulation. Conclusions: The study showed that the administration of extrafine BDP/F improved lung function parameters and hyperinflation. Patients previously treated with ICS remained stable despite the lower dose, while ICS naïve patients improved in terms of lobar hyperinflation. FRI seems to be a sensitive biomarker to detect clinically relevant changes that are not detected by spirometry. The next step is to confirm these findings in a controlled trial.

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

“…Although no direct head-to-head comparisons have been made, the homogeneous improvements in airway volume and resistance in this study appeared to be more uniform than previous FRI studies of other COPD inhalation therapies, including ICS/LABA combinations 1–3. This increase in volume and decrease in resistance across all lobes of the lung led to increased airflow throughout all regions of the lung and may ultimately avoid ventilation/perfusion mismatch due to selective bronchodilation in poorly perfused areas of the lung.…”

“…In other FRI studies of bronchodilators in patients with severe COPD, single doses of the short-acting bronchodilators ipratropium bromide (80 μg) and salbutamol (400 μg) – both double the standard prescribed dose for the treatment of COPD and administered with a valved spacer – showed a ~32% increase in distal airway volume and a ~58% decrease in distal airway resistance, with each treatment compared to pre-dose 2. In addition, single-dose beclomethasone/formoterol 200/12 μg MDI and budesonide/formoterol 160/4.5 μg dry powder inhaler significantly increased airway volume by around 10% (siVaw vs baseline and iVaw vs placebo) and reduced airway resistance by around 35% (siRaw vs baseline) and 16% (iRaw difference from placebo), respectively, in patients with COPD 1,3…”

“…FRI is considered a more sensitive method of investigating pharmacologically induced changes in the lungs than classical lung function tests 1–3. This image-based method opens up the possibility of providing a comprehensive assessment of airway tree changes both centrally and distally1,2 and has been used to detect regional changes in the 3D airway geometry in patients with COPD following bronchodilator treatment and to provide insights into the physiological effects of bronchodilators 1–3. FRI can generate functional data about airflow and drug deposition throughout the lobes of the lung.…”

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…Spray characterization of MDIs using CFD is challenging because of the several physical processes that include droplet formation, the large temperature gradient at the device orifice, high initial velocity values, and rapid evaporation of the propellant . Several studies have considered MDI delivery to the lungs using CFD, with varying physical treatments . Proper characterization of an MDI spray requires the careful selection of orifice boundary conditions because this process is crucial to understanding device differences.…”

“…specified a value of 215 K to the injected droplets, which subsequently cooled the surrounding air. For several studies, it is unclear what, if any, treatment for heat transfer was applied . Studies conducted by Gavtash et al .…”