BACKGROUND: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity.
METHODS: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses.
RESULTS: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD.
CONCLUSIONS: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations.
BACKGROUND: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

BACKGROUND: Previous studies have reported reduced acute exacerbation rates and improved symptom control in asthma patients treated using inhaled corticosteroids plus formoterol maintenance and reliever therapy (MART). Fluticasone furoate (FF) and vilanterol (VIL) also provide rapid bronchodilation and sustained anti-inflammatory effects, however no studies have investigated FF/VIL as MART for asthma control.
METHODS: From October 1, 2021 to September 30, 2023, this retrospective study included asthma patients classified as step 3 or 4 according to the Global Initiative for Asthma guidelines, who were then divided into two groups. One group received BUD/FOR as MART, while the other received FF/VIL as MART. Pulmonary function tests, exacerbation rates, Asthma Control Test (ACT), fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts were measured before and after 12 months of treatment.
RESULTS: A total of 161 patients were included, of whom 36 received BUD/FOR twice daily as MART, and 125 received FF/VIL once daily as MART. After 12 months of treatment, the FF/VIL group showed a significant increase in ACT scores by 1.57 (p < 0.001), while the BUD/FOR group had an increase of 0.88 (p = 0.11). In terms of FeNO levels, the BUD/FOR group experienced a decline of -0.2 ppb (p = 0.98), whereas the FF/VIL group had a mild increase of + 0.8 ppb (p = 0.7). Notably, there was a significant difference in the change of FeNO between the two groups (∆ FeNO: -0.2 ppb in BUD/FOR; + 0.8 ppb in FF/VIL, p < 0.001). There were no significant alterations observed in FEV1, blood eosinophil count, or acute exacerbation decline in either group.
CONCLUSIONS: In the current study, patients treated with FF/VIL as MART showed improvements in ACT scores, while those treated with BUD/FOR as MART exhibited a reduction in FeNO levels. However, the difference between the two treatment groups did not reach clinical significance. Thus, FF/VIL as MART showed similar effectiveness to BUD/FOR as MART.

UNASSIGNED: To evaluate the cost-effectiveness of budesonide/formoterol reliever and maintenance therapy compared with salmeterol/fluticasone plus salbutamol as reliever therapy for asthma patients ≥12 years from the societal perspective in China.
UNASSIGNED: A Markov model was developed with three health states (non-exacerbation, exacerbation, and death) with a lifetime horizon. The exacerbation rates were obtained from a prospective cohort study conducted in Chinese asthma patients. Healthcare resources utilization data were estimated based on current clinical asthma management guidelines. Asthma-related mortality, cost input and utility values were derived from public database and literature. Model robustness was assessed with one-way sensitivity and probabilistic sensitivity analyses.
UNASSIGNED: Compared with salmeterol/fluticasone plus salbutamol, budesonide/formoterol reliever and maintenance therapy led to fewer exacerbation events (13.6 vs. 15.9) and 0.0077 quality-adjusted life years (QALY) gain at an additional cost of ¥196.38 over lifetime. The base case incremental cost-effectiveness ratio (ICER) was ¥25,409.98 per QALY gained. The variables that had most impact on the model output included drug costs and medication adherence. At a willingness-to-pay threshold of ¥257,094/QALY (3 times of gross domestic product per capita in China in 2022), the probability of budesonide/formoterol maintenance and reliever therapy being cost-effective versus salmeterol/fluticasone plus as-needed salbutamol was 83.00%.
UNASSIGNED: From the societal perspective, budesonide/formoterol reliever and maintenance therapy is likely to be a cost-effective option compared with salmeterol/fluticasone plus as-needed salbutamol for Chinese asthma patients ≥12 years.

UNASSIGNED: The extrafine single inhaler triple therapy (efSITT) containing beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg has proved to be efficacious in patients with chronic obstructive pulmonary disease (COPD) in randomized control trials.
UNASSIGNED: TRIWIN study evaluated the effectiveness of efSITT delivering beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 μg in COPD patients previously treated with multiple-inhaler triple therapy (MITT) in a real-world study in Greece.
UNASSIGNED: Prospective, multicenter, observational, non-interventional study was conducted over 24 weeks.
UNASSIGNED: A total of 475 eligible patients had moderate-to-severe COPD, an indication for treatment with efSITT, and were symptomatic despite receiving MITT. COPD Assessment Test (CAT) score, pulmonary function parameters, use of rescue medication, and adherence to inhaler use were recorded at baseline (Visit 1), 3 (Visit 2), and 6 months (Visit 3) after treatment.
UNASSIGNED: Mean CAT score decreased from 21.4 points at Visit 1, to 16.6 at Visit 2 and 15.1 at Visit 3 (p < 0.001 for all pair comparisons). At Visit 3, 79.8% of patients reached a CAT improvement exceeding minimal clinically important difference (⩾2), compared to baseline. Mean forced expiratory volume in 1 s (%pred.) increased from 55.4% at Visit 1 to 63.5% at the end of study period (p < 0.001), while mean forced vital capacity (%pred.) increased from 71.1% at Visit 1, to 76.7% at Visit 3 (p < 0.001). The mean Test of Adherence to Inhalers score increased from 42.5 to 45.3 and 46.3 points, for the three visits, respectively (p < 0.001 comparing Visits 1/2 and Visits 1/3; p = 0.006 comparing Visits 2/3). The percentage of patients showing good adherence rose from 33.7% at baseline to 58.3% at Visit 3. The percentage of patients using rescue medication during the last month dropped from 16.2% to 7.4% at the end of study period (p < 0.001). Pulmonary function parameters also improved.
UNASSIGNED: The TRIWIN results suggest that extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium is effective in improving health status, pulmonary function, and adherence and in reducing rescue medication use in COPD patients previously treated with MITT, in a real-world setting in Greece.

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of \'inhalation biopharmaceutics\' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using \'simple\' Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.

BACKGROUND: Short-acting β2-agonists (SABA) overuse is associated with poor asthma control. The Global Initiative for Asthma (GINA) 2019-updated strategy report has therefore taken a paradigm shift in reliever therapy recommendations.
OBJECTIVE: (I) To investigate the status of SABA overuse and medication dispensing patters in asthma in the Netherlands (II) validate dispensing data for SABA overuse identification and (III) understand patients\' perspectives towards this SABA-taking behavior to inform future improvement strategies.
METHODS: An annually repeated cross-sectional study was conducted from 2017 to 2021 using pharmacy dispensing data in a real-world setting, including asthma patients aged 18-45 with ≥1 inhaler. A following qualitative study was performed in identified SABA overusing patients with a questionnaire and semi-structured interviews, supported by theoretical frameworks.
RESULTS: Dispensing data was available from 87 % of all community pharmacies (n = 1994) in 2017 and 95 % (n = 2005) in 2021. SABA overuse prevalence was constant for the five study-years with 20.6 % (±0.5 %). Increased ICS-formoterol and decreased SABA dispenses were observed in starters of inhalation therapy in 2021. 53 asthma patients completed the questionnaire of whom 43 patients confirmed SABA overuse, generating a positive predictive value of 81 %. Key behavioral drivers covered 7 themes regarding capability (knowledge; skills; memory, attention and decision process) motivation (emotion; beliefs about-capabilities; consequences) and opportunity (environmental context).
CONCLUSIONS: SABA overuse remains in one-fifth of asthma patients across the Netherlands, requiring careful attention from healthcare professionals. Dispensing data is a valid measure for SABA overuse in a clinical setting, facilitating patient selection. To meet patients\' varied supporting needs, integration of tailored behavioral interventions is essential.

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BACKGROUND: Podocytes have a remarkable ability to recover from injury; however, little is known about the recovery mechanisms involved in this process. We recently showed that formoterol, a long-acting β2-adrenergic receptor (β2-AR) agonist, induced mitochondrial biogenesis (MB) in podocytes and led to renoprotection in mice. However, it is not clear whether this effect was mediated by formoterol acting through the β2-AR or if it occurred through \"off-target\" effects.
METHODS: We genetically deleted the β2-AR specifically in murine podocytes and used these mice to determine whether formoterol acting through the podocyte β2-AR alone is sufficient for recovery of renal filtration function following injury. The podocyte-specific β2-AR knockout mice (β2-ARfl/fl/PodCre) were generated by crossing β2-AR floxed mice with podocin Cre (B6.Cg-Tg(NPHS2-cre)295Lbh/J) mice. These mice were then subjected to both acute and chronic glomerular injury using nephrotoxic serum (NTS) and adriamycin (ADR), respectively. The extent of injury was evaluated by measuring albuminuria and histological and immunostaining analysis of the murine kidney sections.
RESULTS: A similar level of injury was observed in β2-AR knockout and control mice; however, the β2-ARfl/fl/PodCre mice failed to recover in response to formoterol. Functional evaluation of the β2-ARfl/fl/PodCre mice following injury plus formoterol showed similar albuminuria and glomerular injury to control mice that were not treated with formoterol.
CONCLUSIONS: These results indicate that the podocyte β2-AR is a critical component of the recovery mechanism and may serve as a novel therapeutic target for treating podocytopathies.

BACKGROUND: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a.
METHODS: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC0-t) for the analytes were between 80 and 125 %.
RESULTS: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0-t). In Study 1, GB AUC0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0-t, although not for Cmax. Both formulations were similarly well tolerated in all three studies.
CONCLUSIONS: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.