gsk573719 and Asthma

There is increasing evidence that tiotropium, a long-acting muscarinic agent (LAMA), is useful in the presence of severe-uncontrolled asthma despite the optimization of therapy with inhaled corticosteroids (ICSs) and long-acting β. We have conducted an extensive search on muscarinic antagonists in asthma therapy throughout several sources and discuss what has emerged in the last 3 years (January 2017-March 2020).. New evidence indicates that the effectiveness of adding a LAMA, at least tiotropium, is independent of the degree of the type 2 inflammation and age of patient. Therefore, tiotropium can be administered without the need for patient phenotyping. Umeclidinium and glycopyrronium also appear effective in asthma. Initial treatment with LAMA+ICS for those with mild asthma may be an equally effective therapeutic option as LABA+ICS but this hypothesis should be confirmed by statistically powered trials.

Topics: Adrenal Cortex Hormones; Asthma; Drug Therapy, Combination; Glycopyrrolate; Humans; Muscarinic Antagonists; Quinuclidines; Tiotropium Bromide

Smooth muscle cell contraction in the airways is the principal therapeutic target in asthmatic subjects and its insufficient treatment is often a cause of uncontrolled disease. For this reason, research has focused on targeting smooth muscle activity with anticholinergic agents, including umeclidinium. Areas covered: This review highlights the potential application of umeclidinium, a long acting muscarinic antagonist, as a novel therapeutic approach for patients with severe uncontrolled asthma, despite maximal therapy. Expert opinion: Umeclidinium, similarly to tiotropium, which has been recently included in guidelines, may act by contrasting cholinergic activation in airways, preventing or at least reducing smooth muscle cells contraction and the consequent bronchoconstriction. This is similar to what occurs in chronic obstructive pulmonary disease, for which umeclidinium has been regularly approved. However, available data is not sufficient and further studies are needed before regulatory approval can be sought, since only phase II clinical trials have been conducted at present. Both quality of life and objectifiable clinical data and parameters must be assessed, including lung function improvements, reduction of exacerbations and reduction of as required medications.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Humans; Muscarinic Antagonists; Quality of Life; Quinuclidines; Respiratory Function Tests

Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Clinical Trials as Topic; Drug Discovery; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukotriene Antagonists; Long-Term Care; Macrolides; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Protein Kinase Inhibitors; Quinuclidines; Small Molecule Libraries; Tiotropium Bromide

Blood samples were obtained from the phase IIIA CAPTAIN study (ClinicalTrials.gov: NCT02924688), which evaluated the efficacy and safety of once-daily FF/UMEC/VI versus FF/VI in patients with uncontrolled asthma taking ICS/LABA. Samples were collected at trough (defined as ≥ 20 h after the last dose) from all subjects randomized to the six treatment groups (FF/UMEC/VI 100/31.25/25 μg, 100/62.5/25 μg, 200/31.25/25 μg, 200/62.5/25 μg; FF/VI 100/25 μg, 200/25 μg) at week 24 or the early withdrawal visit. In a subset of patients, PK samples were obtained predose at week 12, and at 5-30 min, 45-90 min, and 2-3 h postdose. For each analyte, a population PK model was developed using non-linear mixed-effects modeling. The maximum likelihood method was utilized to incorporate data below the quantifiable limit (BQL). Final models were used to derive the area under the plasma concentration-time curve and maximum observed concentration at steady-state for each analyte.. We obtained 4018, 2695, and 4032 samples from 1891, 1258, and 1891 patients, for FF, UMEC, and VI, respectively; 48%, 49%, and 50% of samples were reported as BQL for each analyte, respectively. The PK were adequately described by a two-compartment model with first-order absorption and elimination for FF, a two-compartment model with intravenous bolus input and first-order elimination for UMEC, and a three-compartment model with zero-order input and first-order elimination for VI. Statistically significant covariates were body weight on apparent inhaled clearance of FF, creatinine clearance on apparent clearance and body weight on apparent inhaled volume of distribution of the central compartment for UMEC, and race (East Asian, Japanese, and South East Asian heritage) on inhaled apparent volume of distribution of the central compartment for VI. However, the overall effects of covariates were marginal and thus do not warrant dose adjustment. Systemic exposures of FF or VI did not differ when administered as a single-inhaler triple (FF/UMEC/VI) or dual combination (FF/VI), and were similar to those reported for patients with chronic obstructive pulmonary disease.. Only marginal covariate effects were observed, and thus no dose adjustments are deemed necessary for FF, UMEC, or VI. There was no difference in FF or VI systemic exposure in patients with asthma when administered as either triple (FF/UMEC/VI) or dual therapy (FF/VI). Together with efficacy findings from the CAPTAIN study, our data support the use of single-inhaler FF/UMEC/VI triple therapy for patients with uncontrolled asthma currently receiving ICS/LABA.

Topics: Administration, Inhalation; Androstadienes; Asthma; Benzyl Alcohols; Bromides; Chlorobenzenes; Double-Blind Method; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

Patients with asthma uncontrolled on inhaled corticosteroids may benefit from umeclidinium (UMEC), a long-acting muscarinic antagonist.. This Phase IIb, double-blind study included patients with reversible, uncontrolled/partially-controlled asthma for ≥6 months, receiving ≥100 mcg/day fluticasone propionate (or equivalent) for ≥12 weeks. Following a 2-week run-in on open-label fluticasone furoate (FF) 100 mcg, patients were randomised (1:1:1) to receive UMEC 31.25 mcg, UMEC 62.5 mcg or placebo on top of FF 100 mcg once-daily for 24 weeks. As-needed salbutamol was provided. Primary and secondary endpoints were change from baseline in clinic trough forced expiratory volume in 1 s (FEV. The intent-to-treat population comprised 421 patients (UMEC 31.25 mcg: n =139, UMEC 62.5 mcg: n =139, placebo: n =143). UMEC 31.25 mcg and 62.5 mcg demonstrated significantly greater improvements from baseline in clinic trough FEV. UMEC is a highly effective bronchodilator that leads to improved lung function when administered as a single bronchodilator on top of FF in subjects with fully reversible, uncontrolled/partially-controlled moderate asthma. These data support a favourable benefit/risk profile for UMEC (31.25 mcg and 62.5 mcg).. GSK study ID: 205832; Clinicaltrials.gov ID: NCT03012061.

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Quinuclidines; Treatment Outcome

Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is of increasing interest because ACO patients have significantly worse outcomes, leading to greater social and economic burdens compared with asthma or COPD alone. Some guidelines for ACO recommend triple therapy with inhaled corticosteroids, long-acting β2 agonists, and long-acting muscarinic antagonists. However, this approach is based on extrapolating data from patients with asthma or COPD alone. Therapeutic studies for ACO have not previously been conducted.. A 12-week, randomized, open-label cross-over pilot study was conducted in 17 ACO patients to evaluate the effect of umeclidinium (UMEC) 62.5 µg once-daily added to fluticasone furoate/vilanterol (FF/VI) 200/25 µg once-daily. A 4-week run-in, a first and a second 4-week treatment period were included. Respiratory function, respiratory impedance, fractional exhaled nitric oxide, COPD assessment test, and asthma control test scores were evaluated 0, 4, and 8 weeks after randomization.. Adding UMEC to FF/VI provides greater improvement in lung function, indicating that triple therapy is a suitable regular treatment for ACO.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cross-Over Studies; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Japan; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Treatment Outcome

The long-acting muscarinic antagonist, umeclidinium (UMEC), combined with the inhaled corticosteroid, fluticasone furoate (FF), improves lung function in symptomatic patients with asthma. We assessed FF/UMEC in patients with a primary diagnosis of asthma or chronic obstructive pulmonary disease (COPD), but physiological characteristics of both (fixed airflow obstruction and reversibility to salbutamol).. This double-blind, parallel-arm, 3-phase study randomised 338 patients (1:1:1:1:2:2) to FF 100 mcg alone or combined with UMEC (15.6, 62.5, 125, or 250 mcg) or vilanterol 25 mcg (Phase A, 4 weeks). Primary endpoint: change from baseline in clinic trough forced expiratory volume in 1 s (FEV

Topics: Adult; Aged; Albuterol; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Muscarinic Antagonists; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Quinuclidines

To our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS).. Evaluate the dose-response, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS.. In this double-blind, three-period crossover study, 350 subjects were randomized to a sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250 mcg once daily (OD), UMEC 15.6 or 31.25 mcg twice daily (BID), or placebo, administered for 14 days (12-14-day washout). Trough forced expiratory volume in one second (FEV1), 0-24-h weighted mean (WM) FEV1, and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup.. Subjects had a mean baseline pre- and post-bronchodilator FEV1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 OD (0.066 L; p = 0.036) and UMEC 125 OD (0.088 L; p = 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0-24-h WM FEV1 versus placebo (0.068-0.121 L [p ≤ 0.017] with no clear dose-response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9-21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters.. The modest trough FEV1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma.. NCT01641692.

Topics: Administration, Inhalation; Adolescent; Adult; Asthma; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Quinuclidines; Treatment Outcome; Young Adult

In two dose-ranging crossover studies, the long-acting muscarinic antagonist umeclidinium (UMEC) was assessed as monotherapy in patients with asthma not treated with inhaled corticosteroids (ICS) (NCT01641692 [study 1]) and combined with the ICS fluticasone furoate (FF) in patients with asthma symptomatic on ICS (NCT01573624 [study 2]). The present study aimed to further characterise the UMEC dose-response relationship with change from baseline trough forced expiratory volume in one second (FEV1) (day 15).. A model-based approach using non-linear mixed-effects analyses was used to assess data from studies 1 and 2.. Within the Study 1 dose range, no significant dose-response was demonstrated. In study 2, the slope-intercept on log-dose model showed a mild dose-response, with a 10 % probability of a 0.075-L FEV1 improvement with FF/UMEC 100/250 mcg; period 1 data (with an absent carryover effect) indicated an 88 % probability of a 0.075-L FEV1 improvement.. The model-based approach in study 2 identified FF/UMEC doses warranting further investigation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Asthma; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Nonlinear Dynamics; Quinuclidines

Topics: Androstadienes; Asthma; Benzyl Alcohols; Chlorobenzenes; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

Topics: Androstadienes; Asthma; Benzyl Alcohols; Chlorobenzenes; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines

To evaluate the in vitro dose delivery characteristics of approved asthma and chronic obstructive pulmonary disease (COPD) therapies delivered via the ELLIPTA(®) dry powder inhaler across inhalation endpoints representative of the target patient population, using the Electronic Lung (eLung™) to replicate inhaler-specific patient inhalation profiles that were previously recorded in vivo.. Selected profiles, representative of the range of inhalation endpoints achieved by patients with all severities of asthma and COPD, were replicated using the eLung breathing simulator in conjunction with an oropharyngeal cast. A Next Generation Impactor was coupled to the eLung to determine the aerodynamic particle size distribution of the ex-throat dose (ETD) of asthma and COPD therapies delivered via the ELLIPTA inhaler. Delivered dose (DD), ETD, and fine particle dose (FPD; defined as a mass of active substance less than 5 μm) were determined for fluticasone furoate (FF)/vilanterol (VI) 100/25 μg and 200/25 μg (asthma and COPD), umeclidinium (UMEC)/VI 62.5/25 μg (COPD only), FF 100 μg and 200μg monotherapy (asthma only), and UMEC 62.5 μg monotherapy (COPD only).. Inhalation profiles replicated by eLung covered a wide range of peak inspiratory flow rates (41.6-136.9 L/min), pressure drops (1.2-13.8 kPa), and inhaled volumes through the inhaler (0.7-4.2L). DD was consistent across the range of patient representative inhalation parameters for all components (FF, VI, and UMEC) of each therapy assessed; although ETD and FPD were also generally consistent, some small variation was observed. Dose delivery was consistent for each of the components, whether delivered as mono- or combination therapy.. The in vitro performance of the ELLIPTA inhaler has been demonstrated for the delivery of FF/VI, UMEC/VI, FF monotherapy, and UMEC monotherapy. Across a range of inspiratory profiles, DD was consistent, while ETD and FPD showed little flow dependency.

Topics: Administration, Inhalation; Aerosols; Androstadienes; Asthma; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Clinical Trials as Topic; Drug Combinations; Drug Delivery Systems; Dry Powder Inhalers; Equipment Design; Humans; Inhalation; Lung; Models, Anatomic; Models, Biological; Powders; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Severity of Illness Index