Pharmacokinetic Bioequivalence between Generic and Originator Orally Inhaled Drug Products: Validity of Administration of Doses above the Approved Single Maximum Dose.

Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA's "weight of evidence" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.

Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study.

INTRODUCTION: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. METHODS: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. RESULTS: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. CONCLUSION: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Progression of Acute Lung Injury in Intratracheal LPS Rat Model: Efficacy of Fluticasone, Dexamethasone, and Pirfenidone.

INTRODUCTION: We investigated the potential of LPS (10-300 µg/rat) administered intratracheally (i.t.) to induce reproducible features of acute lung injury (ALI) and compared the pharmacological efficacy of anti-inflammatory glucocorticoids and antifibrotic drugs to reduce the disease. Additionally, we studied the time-dependent progression of ALI in this LPS rat model. METHODS: We conducted (1) dose effect studies of LPS administered i.t. at 10, 30, 100, and 300 µg/rat on ALI at 4 h timepoint; (2) pharmacological interventions using i.t. fluticasone (100 and 300 µg/rat), i.t. pirfenidone (4,000 µg/rat), and peroral dexamethasone (1 mg/kg) at 4 h timepoint; (3) kinetic studies at 0, 2, 4, 6, 8, 10, and 24 h post-LPS challenge. Phenotype or pharmacological efficacy was assessed using predetermined ALI features such as pulmonary inflammation, edema, and inflammatory mediators. RESULTS: All LPS doses induced a similar increase of inflammation, edema, and inflammatory mediators, e.g., IL6, IL1ß, TNFα, and CINC-1. In pharmacological intervention studies, we showed fluticasone and dexamethasone ameliorated ALI by inhibiting inflammation (>60-80%), edema (>70-100%), and the increase of cytokines IL6, IL1ß, and TNFα (≥70-90%). We also noticed some inhibition of CINC-1 (25-35%) and TIMP1 (57%) increase with fluticasone and dexamethasone. Conversely, pirfenidone failed to inhibit inflammation, edema, and mediators of inflammation. Last, in ALI kinetic studies, we observed progressive pulmonary inflammation and TIMP1 levels, which peaked at 6 h and remained elevated up to 24 h. Progressive pulmonary edema started between 2 and 4 h and was sustained at later timepoints. On average, levels of IL6 (peak at 6-8 h), IL1ß (peak at 2-10 h), TNFα (peak at 2 h), CINC-1 (peak at 2-6 h), and TGFß1 (peak at 8 h) were elevated between 2 and 10 h and declined toward 24 h post-LPS challenge. CONCLUSION: Our data show that 10 µg/rat LPS achieved a robust, profound, and reproducible experimental ALI phenotype. Glucocorticoids ameliorated key ALI features at the 4-h timepoint, but the antifibrotic pirfenidone failed. Progressive inflammation and sustained pulmonary edema were present up to 24 h, whereas levels of inflammatory mediators were dynamic during ALI progression. This study's data might be helpful in designing appropriate experiments to test the potential of new therapeutics to cure ALI.

Umeclidinium plus vilanterol versus fluticasone propionate plus salmeterol for chronic obstructive pulmonary disease: a meta-analysis of randomized, controlled trials.

PURPOSE: Umeclidinium plus vilanterol (UMEC/VI) is an inhaled long-acting muscarinic antagonist/long-acting beta2-agonist (LAMA/LABA), recently approved as once-daily maintenance therapy for chronic obstructive pulmonary disease (COPD). This meta-analysis aims to assess the efficacy and safety of UMEC/VI compared with fluticasone propionate plus salmeterol (FP/SAL). METHODS: A systematic search was conducted by a trained medical research librarian across MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Chinese Biomedical Literature Database (CBM) for randomized controlled trials comparing UMEC/VI with FP/SAL in COPD patients. Two reviewers independently assessed the risk of bias and extracted data. The primary outcome was 0-24 h weighted mean (wm) forced expiratory volume in the first second (FEV1), trough FEV1. The secondary outcomes were other lung functions, symptoms, quality of life, and safety. RESULTS: Three studies with 2119 patients were included in the meta-analysis. UMEC/VI showed improvement in 0-24 h wm FEV1 (mean difference (MD) 0.08 L, 95% confidence interval (CI) 0.06 to 0.10, P < 0.01, moderate quality) and trough FEV1 (MD 0.09 L, 95% CI 0.07 to 0.11, P < 0.01, moderate quality) in comparison with FP/SAL. UMEC/VI statistically significantly improved all other lung functions compared with FP/SAL. However, there were no significant differences between UMEC/VI and FP/SAL in rescue-medication use, symptomatic endpoints, and health outcomes. UMEC/VI also demonstrated fewer drug-related adverse effects (risk ratio 0.47, 95% CI 0.27 to 0.82, P = 0.01, low quality). CONCLUSIONS: UMEC/VI, when compared with FP/SAL, demonstrated significant improvements in lung functions with fewer drug-related adverse effects. However, the conclusion was limited by the scarcity of studies and long-term trials.

Comparative Efficacy of Budesonide/Formoterol Versus Fluticasone/Salmeterol in Patients With Moderate-to-Severe Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVE: To compare the efficacy of budesonide/formoterol (BF) versus fluticasone/salmeterol (FS) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for studies comparing BF versus FS in the treatment of COPD from inception to July 17, 2023. Outcomes, including exacerbations, hospitalizations, pneumonia, emergency department (ED) visits for COPD, length of hospitalization, and number of exacerbations, were compared using risk ratio (RR) with corresponding 95% confidence interval (CI) or weighted mean difference (WMD) with 95% CI. All statistical analyses were performed using Stata version 12.0. RESULTS: Ten studies comprising a total of 136,369 participants were included. Compared with those treated with FS, patients with COPD treated with BF experienced a reduced number of exacerbations (RR 0.91 [95% CI 0.83-1.00]; p = 0.040), hospitalizations (RR 0.77 [95% CI 0.67-0.88]; p < 0.001), and frequency of pneumonia (RR 0.77 [95% CI 0.64-0.92]; p = 0.05). However, no significant difference was observed between BF and FS in terms of ED visits for COPD (RR 0.87 [95% CI 0.69-1.10]; p = 0.243), length of hospitalization (WMD -0.18 [95% CI -0.62-0.27]; p = 0.437), and number of exacerbations (WMD -0.06 [95% CI -0.28-0.16]; p = 0.602). Notably, no significant heterogeneity was noted in length of hospitalization between the two groups, whereas clear heterogeneity was observed in other outcomes (I2 > 50%, p < 0.05). CONCLUSION: Compared with FS, BF therapy appears to be a more promising treatment strategy for patients with moderate-to-severe COPD; however, this should be verified in further high-quality studies.

Modeled small airways lung deposition of two fixed-dose triple therapy combinations assessed with in silico functional respiratory imaging.

BACKGROUND: Small airways disease plays a key role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and is a major cause of obstruction; therefore, it is a critical pharmacotherapy target. This study evaluated lung deposition of two inhaled corticosteroid (ICS)/long-acting ß2-agonist/long-acting muscarinic antagonist single-inhaler triple therapies using in silico functional respiratory imaging (FRI). Deposition was assessed using real-world inhalation profiles simulating everyday use where optimal inhalation may be compromised. METHODS: Three-dimensional airway models were produced from 20 patients with moderate-to-very severe COPD. Total, central, and regional small airways deposition as a percentage of delivered dose of budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) 160/7.2/5 µg per actuation and fluticasone furoate/umeclidinium/vilanterol (FF/UM/VI) 100/62.5/25 µg were evaluated using in silico FRI based on in vitro aerodynamic particle size distributions of each device. Simulations were performed using multiple inhalation profiles of varying durations and flow rates representing patterns suited for a pressurized metered-dose inhaler or dry-powder inhaler (four for BGF, two for FF/UM/VI, with one common profile). For the common profile, deposition for BGF versus FF/UM/VI was compared post-hoc using paired t-tests. RESULTS: Across inhalation profiles, mean total lung deposition was consistently higher with BGF (47.0-54.1%) versus FF/UM/VI (20.8-22.7%) and for each treatment component, with greater deposition for BGF also seen in the central large airways. Mean regional small airways deposition was also greater across inhalation profiles with BGF (16.9-23.6%) versus FF/UM/VI (6.8-8.7%) and for each treatment component. For the common profile, total, central, and regional small airways deposition were significantly greater for BGF versus FF/UM/VI (nominal p < 0.001), overall and for treatment components; notably, regional small airways deposition of the ICS components was approximately five-fold greater with budesonide versus fluticasone furoate (16.1% vs. 3.3%). CONCLUSIONS: BGF was associated with greater total, central, and small airways deposition for all components versus FF/UM/VI. Importantly, using an identical inhalation profile, there was an approximately five-fold difference in small airways deposition for the ICS components, with only a small percentage of the ICS from FF/UM/VI reaching the small airways. Further research is needed to understand if the enhanced delivery of BGF translates to clinical benefits.

Modelling ASthma TrEatment Responses (MASTER): Effect of individual patient characteristics on the risk of exacerbation in moderate or severe asthma: A time-to-event analysis of randomized clinical trials.

AIMS: There is limited understanding of how clinical and demographic characteristics are associated with exacerbation risk in patients with moderate-to-severe asthma, and how these factors correlate with symptom control and treatment response. Here we assess the relationship between baseline characteristics and exacerbation risk during regular dosing with inhaled corticosteroids (ICS) monotherapy or in combination with long-acting beta2-agonists (ICS/LABA) in clinical trial patients with varying levels of symptom control, as assessed by the asthma control questionnaire (ACQ-5). METHODS: A time-to-event model was developed using pooled patient data (N = 16 282) from nine clinical studies [Correction added on 26 July 2023, after first online publication: The N value in the preceding sentence has been corrected in this version.]. A parametric hazard function was used to describe the time-to-first exacerbation. Covariate analysis included the assessment of the effect of seasonal variation, clinical and demographic baseline characteristics on baseline hazard. Predictive performance was evaluated by standard graphical and statistical methods. RESULTS: An exponential hazard model best described the time-to-first exacerbation in moderate-to-severe asthma patients. Body mass index, smoking status, sex, ACQ-5, % predicted forced expiratory volume over 1 s (FEV1 p) and season were identified as statistically significant covariates affecting baseline hazard irrespective of ICS or ICS/LABA use. Fluticasone propionate/salmeterol (FP/SAL) combination therapy resulted in a significant reduction in the baseline hazard (30.8%) relative to FP monotherapy. CONCLUSIONS: Interindividual differences at baseline and seasonal variation affect the exacerbation risk independently from drug treatment. Moreover, it appears that even when a comparable level of symptom control is achieved in a group of patients, each individual may have a different exacerbation risk, depending on their baseline characteristics and time of the year. These findings highlight the importance of personalized interventions in moderate-to-severe asthma patients.

Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 µm, B-3.8 µm and C-3.7 µm; total single dose: 500 µg). Systemic disposition parameter estimates were obtained from published pharmacokinetic data after intravenous dosing to improve robustness. A biphasic pulmonary absorption model, with mucociliary clearance from the slower absorption compartment, and three systemic disposition compartments was most suitable. Rapid absorption, presumably from peripheral lung, had half-lives of 6.9 to 14.6 min. The peripherally deposited dose (12.6 µg) was significantly smaller for formulation A-4.5 µm than for the other formulations (38.7 and 39.3 µg for B-3.8 µm and C-3.7 µm). The slow absorption half-lives ranged from 6.86 to 9.13 h and were presumably associated with more central lung regions, where mucociliary clearance removed approximately half of the centrally deposited dose. Simulation-estimation studies showed that a biphasic absorption model could be reliably identified and that parameter estimates were unbiased and reasonably precise. Bioequivalence assessment of population pharmacokinetics derived central and peripheral lung doses suggested that formulation A-4.5 µm lacked bioequivalence compared to the other formulations both for central and peripheral doses. In contrast, the other fomulations were bioequivalent. Overall, population pharmacokinetics holds promise to provide important insights into the pulmonary fate of inhalation drugs, which are not available from non-compartmental analysis. This supports the assessment of the pulmonary bioequivalence of fluticasone propionate inhaled formulations through pharmacokinetic approaches, and may be helpful for discussions on evaluating alternatives to clinical endpoint studies.

Giant lung cavity due to three different pathogens in a patient receiving inhaled salmeterol plus fluticasone propionate for asthma.

INTRODUCTION: High-dose and long-term use of inhaled corticosteroids may cause systemic and local side effects such as opportunistic infections. Here we report a patient with asthma who developed a giant cavity in the lung while using inhaled salmeterol plus fluticasone propionate. CASE STUDY: A 57-year-old female patient presented with a three-week history of cough, hemoptysis, and dyspnea. She had a diagnosis of asthma for 4 years and was using an inhaled salmeterol plus fluticasone treatment intermittently for 2 years. A giant cavity was detected in the patient's chest X-ray. As a result of further investigations, three different microorganisms were isolated from the samples of sputum, bronchial lavage and lung biopsy. RESULTS: Staphylococcus aureus was the first microorganism that was isolated from the sputum and the bronchial lavage. Afterwards, Candida albicans was detected in both the bronchial lavage fluid and the histologic examination of the tissue samples obtained by percutaneous lung biopsy. Appropriate antibiotics and antifungals were prescribed. Moderate clinical and radiological response to the treatment was obtained. During the outpatient follow-up, Mycobacterium tuberculosis growth which was sensitive to all of the major anti-tuberculosis drugs was reported in the mycobacterial culture, and the patient was started on anti-tuberculosis treatment. CONCLUSION: Tuberculosis and other opportunistic infections are a potential consequences of inhaled corticosteroids. Clinicians overseeing such patients need to be vigilant about the need for timely investigations about tuberculosis before and during prescribing medications containing inhaled corticosteroids.

Fluticasone furoate plus vilanterol in patients with moderate persistent asthma: a cost-utility analysis.

BACKGROUND: In recent years, the combination of fluticasone furoate and vilanterol (FF/VI) has emerged as an alternative therapy, since it is administered every 24 h, in contrast to other ICS/LABAs such as fluticasone propionate plus salmeterol (FP/Salm), which requires administration every 12 h. Concerns have arisen over whether the benefit generated by FF/VI justifies the additional costs it involves over FP/Salm. This study aimed at assessing the health and economic consequences of FF/VI in patients with moderate-severe persistent asthma. METHODS: A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with persistent asthma. Total costs and QALYs for FF/VI and FP/Salm were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000. RESULTS: We estimated a gain of 16.8 and 10.7 QALYs per patient per year on FF/VI and FP/Salm, respectively. At the same time, we observed a difference of US$216 in total discounted cost per person-year on FF/VI with respect to FP/Salm. The incremental cost-effectiveness ratio (ICER) of FF/VI was USD $70 per QALY with respect to FP/Salm. In the deterministic and probabilistic sensitivity analyses, our base-case results were robust to variations in all assumptions and parameters. CONCLUSION: FF/VI is more cost-effective than FP/Salm. The evidence supports using FF/VI therapy in Colombia, and the study should be replicated in other middle-income countries.

The assessment of effectiveness, tolerance, and patient satisfaction with the use of a new fixed-dose combination product, containing salmeterol and fluticasone propionate, Salflumix Easyhaler® in the treatment of asthma in the daily clinical practice.

BACKGROUND: The effectiveness of a fix-dose salmeterol/fluticasone combination therapy in asthma was previously shown for the original product. The study aim was to evaluate the clinical effectiveness and safety of a second entry DPI - dry powder inhaler (Salflumix Easyhaler) in patients with asthma in everyday clinical practice. PATIENTS AND METHODS: This multicenter Investigator-Initiated Study that enrolled 2,037 adult outpatients with asthma treated with Salflumix Easyhaler, was conducted by 220 pulmonologists across Poland. Asthma control was assessed during 3 visits with 6 ± 2 weeks intervals based on the Asthma Control Test (ACT). In addition, patient Satisfaction with Asthma Treatment Questionnaire (SATQ) and adherence and adverse events (AEs) were monitored. RESULTS: During the observation (86 ± 30 days) the percentage of patients with controlled asthma (ACT 20-25 pts) increased from 35.5% at the first visit to 86.5% at the third visit (p < 0.001). In the subgroup analysis, there were more patients not obtaining asthma control among patients that switched from the treatment with other devices than in naive ones. Global SATQ scores increased from 5.8 ± 0.7 to 6.2 ± 0.6 during the observation. Patients' satisfaction with the use of the Salflumix Easyhaler was high. Adherence exceeded 95%. Eight AEs were reported. CONCLUSIONS: Salflumix Easyhaler is highly effective and well-tolerated by naïve patients with asthma and those switching from another device. In general, patients show good compliance with medical product and are satisfied with the use of this new device, and not reporting difficulties and errors related to its' use. Their physicians' overall perception of Salflumix Easyhaler use is very positive.

The clinical efficacy of fluticasone propionate combined with ACEI/ARB in the treatment of immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy worldwide, and lacks the effective treatment. The study was aimed to investigate the clinical efficacy of fluticasone propionate aerosol combined with angiotensin converting enzyme inhibitor / angiotensin receptor blocker (ACEI/ARB) in the treatment of IgAN. METHODS: 142 patients with biopsy-proven IgAN at Shenzhen People?s hospital from June 2018 to June 2020 were enrolled. The patients were randomly divided into the supportive care plus fluticasone group and the supportive care group. The patients of the supportive care plus fluticasone group were treated with fluticasone propionate aerosol (250 ?g Bid) combined with ACEI/ARB, while the supportive care group was merely treated with ACEI/ARB. The patients were followed up at 3, 6 and 9 months after enrollment. Primary outcomes include changes in proteinuria and estimated glomerular filtration rate (eGFR). RESULTS: The level of proteinuria in the supportive care plus fluticasone group was significantly lower compared with the supportive care group at 0, 3, 6 and 9 months. Meanwhile, during the follow-up period, no serious adverse events were recorded during the study in either group. However, fluticasone treatment did not alleviate the decline in eGFR. CONCLUSION: Fluticasone propionate aerosol combined with ACEI/ARB can reduce the level of proteinuria in thetreatment of IgAN, and has no significant effects on renal function.

Bronchodilator reversibility testing in morbidly obese non-smokers: fluticasone/salmeterol efficacy versus salbutamol bronchodilator.

A positive response in reversibility testing is widely used to diagnose patients with airway limitations. However, despite its simple procedure, it doesn't accurately reflect the exact airway irreversibility. This study aimed to investigate the efficacy of a bronchodilation reversibility test using salbutamol and fluticasone/salmeterol combination in obese non-smoker subjects.The study included patients without a history of obstructive lung disease or bronchodilators. A sub-classification of patients based on body mass index (BMI) was carried out into normal (< 24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (BMI ≥ 30). Spirometry measurements were performed before and after salbutamol or fluticasone/salmeterol administration.The study included 415 (49.9% male) patients with a mean age of 40.92 ± 10.86 years. Obese subjects showed a high prevalence of restrictive patterns (23.4%), with non-significantly lower spirometric values compared to normal and overweight subjects (p > 0.05). The magnitude of bronchodilation, as identified by spirometry, following fluticasone/salmeterol was higher in all participants, with a significant increase in obese subjects with a p-value of 0.013, 0.002, and 0.035 for FEV1, FEV1% predicted, and FEV1/FVC, respectively.Fluticasone/salmeterol combination increases FEV1, FEV1% of predicted, and FEV1/FVC ratio than the conventional test using salbutamol inhaler, and it can be a potential candidate for assessment of airway obstruction using reversibility test, especially among the obese population.

An efficacy and safety evaluation of montelukast + fluticasone propionate vs. fluticasone propionate in the treatment of cough variant asthma in children: a meta-analysis.

PURPOSE: This study aimed to evaluate the efficacy and safety of montelukast (Mon) + fluticasone propionate (Flu) versus Flu in the treatment of cough variant asthma (CVA) in children. METHODS: Eligible documents were selected from various databases. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to evaluate continuous variables, and categorical variables were evaluated using risk ratio (RR) and 95% CI. Heterogeneity analysis was performed using Cochran's Q test and I2 statistics, followed by sensitivity analysis and publication bias evaluation. RESULTS: Nine studies were included, and Flu + Mon was found to significantly improve the total effective rate and reduce cough recurrence compared to Flu. The cough remission and disappearance times in the Mon + Flu group were significantly lower than those in the Flu group. FEV1% recovery in the Mon + Flu group was significantly better than that in the Flu group. CONCLUSION: Mon + Flu is effective and safe for the treatment of CVA in children.

Clinical effectiveness of fluticasone furoate nasal spray for perennial allergic rhinitis in children: a comprehensive review.

OBJECTIVE: To assess the clinical effectiveness of fluticasone furoate nasal spray (FFNS) versus placebo on nasal symptoms and safety in children with perennial allergic rhinitis (AR). METHODS: A comprehensive review was conducted with data obtained from Medline and Embase databases up to April 2023. The population of interest was patients aged 2-12 years with perennial AR. The selection was limited to randomized controlled trials (RCTs), comparing FFNS with placebo. Outcomes of interest included the reflective total nasal symptoms scores (rTNSS) and safety. To assess the minimal clinically important difference for rTNSS, the Cohen's guideline was used. If the pooled standardized mean difference (SMD) and the lower limit of the 95 percent confidence interval (CI) exceeded the threshold of -0.20, effects were considered clinically significant. RESULTS: Three RCTs (959 pediatric patients) were selected. One study evaluated the short-term use of FFNS, another evaluated the long-term use of FFNS, and another evaluated both the short-term and long-term use of FFNS. FFNS produced a statistically significant reduction over placebo in rTNSS (SMD -0.18; 95 percent CI -0.35 to -0.01, p = 0.03) in long-term treatment studies, but not in short-term treatment studies. However, since the mean reduction did not reach the minimum clinically important difference (SMD -0.20), these results were considered clinically not relevant. Safety outcomes with FFNS were similar to placebo. CONCLUSIONS: The currently available evidence suggests that FFNS, 110 µg once daily, compared to placebo, does not produce a meaningful clinical effect on nasal symptom in children with perennial AR.

Treatment with Fluticasone Propionate Increases Antibiotic Efficacy during Treatment of Late-Stage Primary Pneumonic Plague.

Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic plague, a severe pneumonia caused by inhalation of Yersinia pestis, is a fatal disease that causes death within 6 days without antibiotic intervention. Late-stage pneumonic plague is difficult to treat, as antibiotics must be delivered within 24 h after onset of symptoms to be effective. Here, we use a murine model of primary pneumonic plague to examine how host inflammatory responses impact antibiotic treatment of late-stage pneumonic plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased the efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of interleukin-6 (IL-6) and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage pneumonic plague and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.

Fluticasone Propionate Orally Disintegrating Tablet (APT-1011) for Eosinophilic Esophagitis: Randomized Controlled Trial.

BACKGROUND & AIMS: Topical steroids are effective treatments for eosinophilic esophagitis (EoE). The FLUTE (Fluticasone in EoE) trial evaluated safety and efficacy of APT-1011 (fluticasone propionate oral disintegrating tablet) vs placebo for treatment of EoE. METHODS: In this randomized, double-blind, placebo-controlled, dose-finding, phase 2b trial, 106 adults with EoE received 1 of 4 APT-1011 doses or placebo for a 12-week induction period and 40 weeks of maintenance. Primary outcome was histologic response (≤6 eosinophils per high-power field) at Week 12. Secondary outcomes included endoscopic features and dysphagia frequency. RESULTS: Histologic response rates were 0% for placebo, 80% for APT-1011 3 mg twice daily (BID), 67% for 3 mg at bedtime (HS), 86% for 1.5 mg BID, 48% for 1.5 mg HS (P < .001 for all groups vs placebo). At Week 12, mean Edema/Rings/Exudates/Furrows/Strictures (EoE Endoscopic Reference Score) total score (max, 9.0) improved from 4.5 to 2.3 for 3 mg BID, 5.3 to 2.1 for 3 mg HS, 4.6 to 1.7 for 1.5 mg BID, 5.3 to 2.9 for 1.5 mg HS vs 5.2 to 4.5 for placebo. Mean dysphagia frequency over 14 days improved from baseline to Week 12 with all active groups improving more than placebo. Improvements were sustained to Week 52. APT-1011 was safe and well-tolerated, with higher incidence of candidiasis noted at the higher twice daily doses. CONCLUSION: APT-1011 dosing regimens were superior for histologic and endoscopic responses, and for reduction in dysphagia frequency vs placebo. Based on the symptom improvement and assessment of adverse events together with the histologic response rate, 3 mg once daily at bedtime dose showed the most favorable risk-benefit profile. CLINICALTRIALS: gov, Number: NCT03191864.

Metabolomic changes related to airway inflammation, asthma pathogenesis and systemic activity following inhaled fluticasone furoate/vilanterol: a randomized controlled trial.

BACKGROUND: Fluticasone furoate/vilanterol trifenatate (FF/VI) is an inhaled therapy for the treatment of asthma, with a prolonged duration of anti-inflammatory and bronchodilatory action. This study investigated the global metabolomic and lipidomic profile following treatment with FF/VI or placebo and assessed whether changes correlated with exhaled nitric oxide levels as a measure of airway inflammation. METHODS: This was a single-center, randomized, double-blind, placebo-controlled, two-period, crossover, repeat-dose study. Adults with asthma (forced expiratory volume in 1 s ≥ 60% predicted; fraction of exhaled nitric oxide [FeNO] > 40 parts per billion) received once-daily FF/VI 100 µg/25 µg or placebo for 14 days, followed by a 21-day washout period. Serum samples were taken at pre-dose (T1), and 15 and 21 days (T2 and T3, respectively) post dose in each period. The metabolomic and lipidomic profiles were analyzed by liquid chromatography with tandem mass spectrometry and polar liquid chromatography platforms, and ions were matched to a library of standards for metabolite identification and quantification. FeNO values at each timepoint were evaluated for correlations with the biochemical data. RESULTS: Of 27 randomized participants (mean age 24.5 years, 63% male), 26 provided serum samples for metabolomic analysis. A total of 1969 metabolites were identified, 1634 of which corresponded to a named structure in a reference library. Treatment-related changes in the metabolome were generally subtle, with a modest increase in metabolite perturbations across timepoints. The percentage of metabolites with significant changes (p < 0.05 for all) (increases↑/decreases↓) versus placebo were: 2.1% (1.1%↑/1.0%↓), 6.7% (0.46%↑/6.2%↓) and 11.8% (0.86%↑/10.9%↓) at T1, T2 and T3, respectively. Treatment with FF/VI reduced FeNO levels by 60%, whereas the systemic intermediates involved in NO biosynthesis remained unaffected. Evidence of systemic anti-inflammatory activity was seen in complex lipid pathways, suggesting reduced phospholipase-A2 activity, but without downstream impact on free fatty acids or inflammatory mediators. Consistent with the pathogenesis of asthma, there was evidence of higher fatty acid ß-oxidation and lower glycolysis in the placebo arm; this pattern was reversed in the treatment arm. CONCLUSIONS: Despite the prolonged airway anti-inflammatory action of FF/VI, this was accompanied by only subtle systemic metabolomic and lipidomic changes. Trial registration Prospectively registered on ClinicalTrials.gov registry number NCT02712047.

Triamcinolone Acetonide in the Treatment of Perennial Allergic Rhinitis: A post hoc Efficacy Analysis of a Phase III Study Performed in Russia.

INTRODUCTION: Allergic rhinitis (AR) is a disease which affects >24% of the population in Russia. Triamcinolone acetonide (TAA) is a corticosteroid used for treating AR. This post hoc analysis assesses the efficacy of intranasal TAA in improving perennial AR (PAR) symptom scores over 4 weeks. METHODS: NASANIF (NCT03317015) was a double-blind, parallel-group, multicenter, prospective, non-inferiority, phase III clinical trial in which patients with PAR were randomized (1:1) to receive TAA or fluticasone propionate (FP) over 4 weeks. Our post hoc analysis evaluates weekly change in PAR symptoms using the reflective Total Nasal Symptom Score (rTNSS), overall and for individual symptoms (sneezing, nasal itching, rhinorrhoea, and nasal obstruction). Proportion of patients and time to achieve a ≥50 or ≥75% reduction in rTNSS were assessed. For rTNSS endpoints, a linear mixed-model methodology was used; for time-to-event endpoints, cumulative incidence functions were estimated using the Kaplan-Meier method, in the per-protocol population. RESULTS: Of 260 patients, 128 each completed the study and were randomized to receive TAA or FP. From baseline to week 4, the changes in total rTNSS were -7.78 (95% CI: -8.1701 to -7.3967; p < 0.001) and -7.52 (-7.9053 to -7.1320; p < 0.001) for TAA and FP, respectively. Individual symptoms improved significantly from baseline. The proportion of patients achieving ≥50 and ≥75% reductions in total rTNSS was 88.0 and 67.2%, respectively in the TAA group. No significant differences were observed between the TAA and FP in any analyses. CONCLUSIONS: TAA produced effective and prolonged improvement of PAR symptoms over a 4-week treatment period.

Comparative clinical pharmacology of mometasone furoate, fluticasone propionate and fluticasone furoate.

AIMS: To investigate the pharmacokinetics and effects on the hypothalamic-pituitary-adrenal (HPA) axis of mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF). METHODS: Study 1: Fourteen healthy participants received inhaled and intravenous MF (inhaled dose via Twisthaler) and FP (inhaled dose via Diskus), both given at 400 µg, using a randomised, single-dose, four-way crossover design. Study 2: Twenty-seven participants with mild to moderate asthma, who discontinued their corticosteroid medication for 5 days to obtain a baseline 24 h serum cortisol, received inhaled MF Twisthaler and FP Diskus, both given at 400 µg twice daily (BID), using a randomised, 14-day repeat dose, two-way crossover design. Study 3: Forty-four healthy participants were randomised to a double-blind, placebo-controlled, five-period crossover study where the following treatments were administered via the inhaled route for 7 days: FP Diskus (250, 500, 1000 µg BID), FF Diskus (100, 200, 400, 800, 1600 µg once daily [QD]) or placebo Diskus. In each study, 24-h serial blood samples were collected and assayed to assess concentrations of MF, 6ß-hydroxy mometasone, mometasone, FP, FF and cortisol. Pharmacokinetic and serum cortisol parameters were estimated as geometric means and 95% confidence intervals (CI). RESULTS: Study 1: For intravenous MF and FP, respectively: absolute bioavailability was 11.4% (95% CI: 7.5, 17.6) and 7.8% (6.3, 9.6); plasma clearance was 47 L/h (41, 52) and 60 L/h (52, 69); half-life was 7.4 h (6.9, 8.0) and 7.2 h (6.5, 8.0); and volume of distribution was 499 L (439, 567) and 623 L (557, 698). Inhalation of single dose MF or FP did not significantly affect serum cortisol (<10% reduction from baseline), whereas intravenous administration of MF or FP each changed serum cortisol by approximately -50% from baseline. Study 2: For MF and FP, respectively: area under the curve up to the last measurable concentration on Day 1 was 421 pg h/mL (270, 659) and 248 pg h/mL (154, 400), and on Day 14 was 1092 pg h/mL (939, 1269) and 591 pg h/mL (501, 696); absolute bioavailability was 12.8% (11.2, 14.2) and 8.9% (7.7, 10.2). On Day 14, 24-h serum cortisol change from baseline was -35% (-44%, -26%) and -18% (-28%, -5%) for MF and FP, respectively; the reduction was significantly greater for MF than FP (ratio for geometric adjusted mean serum cortisol concentration: 1.28 [1.04, 1.56]). Low plasma concentrations of 6ß-hydroxy mometasone were detected after intravenous dosing (Study 1) and after multiple inhaled dosing (Study 2); mometasone was not detected in any samples. Study 3: Inhaled FP and FF had similar systemic bioavailability estimates (12.0% [11.0, 13.2] and 15.0% [12.0, 17.3], respectively), but a differential effect on the HPA axis which was in agreement with the known 1.7-fold higher glucocorticoid receptor-binding affinity of FF versus FP. However, for FP 250 µg BID and FF 100, 200 and 400 µg QD, reduction in serum cortisol was not significantly different from placebo. For higher doses, FP 500 and 1000 µg BID, and FF 800 and 1600 µg QD, changes in serum cortisol concentration relative to placebo were -30%, -70%, -41% and -90%, respectively. Repeat inhaled dosing of FP 1000 µg/day (within the therapeutic dose range) resulted in comparable cortisol suppression to MF in the therapeutic range (30% reduction); whereas for FF this occurred at more than 3-fold above the therapeutic dose range (644 µg/day). CONCLUSIONS: Single inhaled and intravenous doses of MF and FP (400 µg) resulted in similar bioavailability and reductions in serum cortisol. Repeat dosing of inhaled MF and FP in the therapeutic range (800 µg/day) resulted in greater systemic exposure for MF, and a 35% reduction in serum cortisol that was 2-fold greater than for FP. The higher glucocorticoid receptor-binding affinity and bioavailability, lower clearance and the presence of active metabolites may contribute to the greater systemic exposure and effect on cortisol for MF. Repeat dosing of inhaled FP and FF resulted in similar systemic bioavailability but differed in terms of the dose required for comparable cortisol suppression to MF in the therapeutic range. Unlike FP and FF, MF has active metabolites that may contribute to its systemic effects, while device/formulation performance differences also exist between MF-containing products.