Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD

SummaryBackgroundLung mucociliary clearance is impaired in patients with chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend that patients with COPD receive maintenance therapy with long-acting beta-agonists and anticholinergic agents.MethodsTwenty-four patients with mild to moderate COPD received formoterol (12 μg, twice daily from Turbuhaler® dry powder inhaler (DPI)) or tiotropium (18 μg, once daily from Handihaler® DPI) for 14 days. They also received single doses of formoterol, tiotropium, salbutamol (200 μg) and placebo. A radioaerosol technique was used to assess the effects on mucus clearance of 14 days treatment with formoterol or tiotropium, as well as single doses of these drugs.ResultsThe 4 h whole lung retention of radioaerosol was significantly higher after 14 days treatment with tiotropium (P = 0.016), but not after 14 days treatment with formoterol. However, patients bronchodilated after 14 days treatment with both drugs, so that the deposited radioaerosol may have had an increased distance to travel in order to be cleared by mucociliary action. A single dose of formoterol enhanced radioaerosol clearance significantly compared to other single dose treatments (P < 0.05).ConclusionFormoterol (12 μg) enhances mucus clearance in patients with mild to moderate COPD when given as a single dose, and may do so when given for 14 days. Studies of longer duration would be needed in order to assess the effects of the study drugs on mucus clearance when they are used for long-term maintenance therapy

Validation of Radiolabeling of Drug Formulations for Aerosol Deposition Assessment of Orally Inhaled Products

Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man

Lung deposition of BDP/Formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients

BACKGROUND: When inhaling medication, it is essential that drug particles are delivered to all sites of lung inflammation, including the peripheral airways. The aim of this study was to assess the lung deposition and lung distribution of beclomethasone dipropionate (BDP)/formoterol (100/6 μg), both dissolved in hydrofluoroalkane (HFA) and delivered by pressurized metered dose inhaler (pMDI) in healthy subjects, asthmatic, and chronic obstructive pulmonary disease (COPD) patients, to investigate how the in vitro characteristics of the formulation translate into the in vivo performance in diseases with different airway obstruction. METHODS: Healthy volunteers (n = 8), persistent asthmatics (n = 8), and patients with stable COPD (n = 8) completed this open-label, single-dose parallel-group study. Each patient received one single treatment of four puffs of (99 m)Tc-labeled BDP/formoterol formulation. The correlation between particle size distribution of radioactivity and of the drugs in the radiolabeled formulation was validated. Intra- and extrapulmonary deposition, amount of exhaled drug, and the central to peripheral ratio (C/P) were calculated immediately after inhalation. Patients' lung function and pharmacokinetic parameters were also assessed up to 24 h post-dose. RESULTS: The average lung deposition of BDP/formoterol was 34.08 ± 9.30% (relative to nominal dose) in healthy subjects, 30.86 ± 8.89% in asthmatics, and 33.10 ± 8.90% in COPD patients. Extrathoracic deposition was 53.48% ± 8.95, 57.64% ± 9.92 and 54.98% ± 7.01, respectively. C/P ratios of 1.42 ± 0.32 in healthy subjects, 1.96 ± 0.43 in asthmatics, and 1.94 ± 0.69 for COPD patients confirmed drug distribution to all regions of the lungs. Forced expiratory volume in 1 sec (FEV(1)) increased in all groups after BDP/formoterol inhalation, but was more evident in the patient groups. No significant correlation between baseline lung function and drug deposition was observed. Formoterol, BDP, and beclomethasone 17 monopropionate (B17MP) plasma profiles were comparable between groups. CONCLUSION: Inhalation of BDP/formoterol HFA (100/6 μg) produces high and homogeneous deposition of BDP and formoterol in the airways, regardless of pathophysiological condition

Validation of Radiolabeling of Drug Formulations for Aerosol Deposition Assessment of Orally Inhaled Products

Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man