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Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/long-acting ?2-agonists delivered via a pressurized metered-dose inhaler.

ABSTRACT: BACKGROUND:Functional respiratory imaging (FRI) uses three-dimensional models of human lungs and computational fluid dynamics to simulate functional changes within airways and predict the deposition of inhaled drugs. This study used FRI to model the effects of different patient inhalation and drug formulation factors on lung deposition of an inhaled corticosteroid/long-acting ?2-agonist (ICS/LABA) combination, administered by a pressurized metered-dose inhaler. METHODS:Three-dimensional models of the lungs of six patients with asthma (mean forced expiratory volume in 1 s, 83%), treated with an ICS/LABA, were included. FRI modelling was used to simulate (1) the effects on lung deposition of inhalation duration and particle size [fine particle fraction (FPF), proportion of particles <5 µm; and mass median aerodynamic diameter (MMAD), average size of inhalable particles]; (2) deposition of fluticasone propionate/formoterol (FP/FORM) 125/5 µg; and (3) how inhalation profiles and flow rates affected FP/FORM deposition. RESULTS:Total lung depositions (TLDs) following 1-, 3- and 5-s inhalations were 22.8%, 36.1% and 41.6% (metered dose), respectively, and central-to-peripheral deposition (C:P) ratios were 1.81, 0.86 and 0.61, respectively. TLD increased with increasing FPF, from ~8% at 10% FPF to ~36% at 40% FPF (metered dose); by contrast, MMAD had little effect on TLD, which was similar across MMADs (1.5-4.5 µm) at each FPF. FP/FORM deposited throughout central and peripheral airways with gradual (sinusoidal) and sharp (rapid) inhalations. TLD ranged from 35.8 to 44.0% (metered dose) for gradual and sharp inhalations at 30 and 60 L/min mean flow rates. CONCLUSIONS:These data provide important insights into the potential effects of inhalation characteristics (inhalation profile and duration) and aerosol formulation (FPF) on lung deposition of inhaled therapies. FRI thus represents a useful alternative to scintigraphy techniques. Future FRI studies will further our understanding of the deposition of inhaled drugs and help improve the management of asthma.

SUBMITTER: Van Holsbeke C

PROVIDER: S-EPMC5937159 | biostudies-literature | 2018 Jan-Dec

REPOSITORIES: biostudies-literature

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Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/long-acting β2-agonists delivered via a pressurized metered-dose inhaler.

Van Holsbeke Cedric C De Backer Jan J Vos Wim W Marshall Jonathan J

Therapeutic advances in respiratory disease 20180101

<h4>Background</h4>Functional respiratory imaging (FRI) uses three-dimensional models of human lungs and computational fluid dynamics to simulate functional changes within airways and predict the deposition of inhaled drugs. This study used FRI to model the effects of different patient inhalation and drug formulation factors on lung deposition of an inhaled corticosteroid/long-acting β<sub>2</sub>-agonist (ICS/LABA) combination, administered by a pressurized metered-dose inhaler.<h4>Methods</h4> ...[more]

PMID: 29499614

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Project description:IntroductionTriple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA).MethodsA systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St. George's Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12-24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies.ResultsEighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario.ConclusionThis NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.

Project description:BackgroundThis study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).MethodsThis randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 μg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 μg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed.ResultsGP MDI 18, 9, 4.6, and 2.4 μg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0-12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 μg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings.ConclusionsThese efficacy and safety results support GP MDI 18 μg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD.Trial registrationClinicalTrials.gov NCT01566773 . Registered 27 March 2012.

Project description:BackgroundThe effectiveness of metered-dose inhalers (MDIs) in delivering medication to the lungs highly depends on its correct usage technique. Current guidelines state optimal technique for high lung deposition should include a slow inhalation (>5 seconds) at an inspiratory flow rate of 30 L/min and inhaler actuation at the start of inhalation. However, these recommendations were based on clinical studies using CFC (chlorofluorocarbon)-MDIs and in vitro studies of HFA (hydrofluoroalkane)-MDIs using idealized MDI techniques of uniform inhalation and actuation, disregarding the nonuniform techniques of actual patients.MethodsTo better understand the effects of time-varying MDI usage parameters on lung deposition of aerosol delivered by an HFA-MDI, we conducted an in vitro study modeled on real-life variable inspiratory flow and actuation techniques recorded from 15 subjects with asthma/chronic obstructive pulmonary disease (COPD). We developed a model representing the time-varying inspiratory flow waveforms and actuation timings based on 43 MDI techniques recorded from patients. Furthermore, we constructed an in vitro experimental setup using a mouth-throat cast, programmable MDI actuator, and breath simulator to evaluate lung deposition for the MDI techniques derived from our model.ResultsHigh inspiratory flow rates, 60-90 L/min, consistently resulted in high in vitro lung deposition (>40%) of aerosol (albuterol delivered from Ventolin HFA-MDI) compared to 30 L/min when MDI actuation occurred in the first half of inhalation. Also, positive coordination resulted in higher in vitro lung deposition compared with negative or zero coordination (actuating before or at the start of inspiration). Furthermore, variation in coordination affected lung deposition more significantly (23%) than flow rate or duration of inspiration (≤5%).ConclusionsIn an in vitro experimental model based on inhalation data from patients with asthma and COPD, we demonstrated that aerosol lung deposition emitted from Ventolin HFA-MDI is most optimal for MDI actuation in the first half of inspiration at high flow rates (60-90 L/min).

Dataset Information

Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/long-acting ?2-agonists delivered via a pressurized metered-dose inhaler.

Publications

Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/long-acting β2-agonists delivered via a pressurized metered-dose inhaler.

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