Breathomics for Assessing the Effects of Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With COPD

Abstract

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting β2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics.Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 μg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 μg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 μg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 μg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured.Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25−75% and FEV1/FVC (P = 0.008–0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01).Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.

Review of Drug Development Guidance to Treat Chronic Obstructive Pulmonary Disease:USandEUPerspectives

“…For instance, volatile organic compound biomarkers have been shown to correlate with sputum markers from inflammatory cells and cell counts in COPD, and distinct patterns have also been associated with COPD disease staging . In a study analyzing exhaled breath condensate samples from patients with COPD, different biomarker “breathprints” were found after distinct pharmacological interventions, thereby illustrating the potential for therapeutic effect monitoring …”

Pharmacogenomics of chronic obstructive pulmonary disease

“…Metabolomics, the simultaneous assessment of multiple small molecules usually combining liquid chromatography with mass spectrometry, is being increasingly employed in blood samples in large COPD studies [95,96]. Exhaled breath condensate is a promising noninvasive sample for COPD metabolomics [97]. Metabolomics may have several potential roles in COPD pharmacogenomics research, beyond increasing our understanding of disease mechanisms, pathways, and drug targets.…”

Fixed‐dose combination of umeclidinium and vilanterol for patients with chronic obstructive pulmonary disease: A systematic review

“…Blockade of muscarinic M3 receptors by LAMA might result in anti‐inflammatory effects in the airways; such effects might be increased by concomitant activation of beta2 receptors by LABA . However, clinical studies including airway inflammatory biomarkers in patients with COPD are required to assess these pharmacological effects …”