Lung Deposition of Tanimilast, an Inhaled Phosphodiesterase-4 Inhibitor, Assessed by Functional Respiratory Imaging in Asthma and COPD

Abstract Rationale: Tanimilast is an inhaled Phosphodiesterase-4 Inhibitor under development for treatment of asthma and COPD administered via NEXThaler, a dry powder inhaler. Functional Respiratory Imaging (FRI) is a validated technique (De Backer JW et al. 2010), combining HRCT scans of patients with in silico computational flow simulations to calculate aerosol deposition in the airways. This study investigated the intrathoracic deposition patterns of two strengths of tanimilast in asthma and COPD patients via FRI using 3 different inhalation profiles. Method: Intrathoracic deposition of tanimilast (400 µg, 800 µg strengths) was assessed retrospectively in asthma and COPD patients selected from FLUIDDA's database per specified criteria (e.g., reduced lung function but stable disease when CT scan acquired, no disease overlap and predominantly chronic bronchitis in COPD). Intrathoracic deposition results include data for central (trachea and main bronchi), distal (>2 mm in diameter), and peripheral (≤2 mm in diameter) airways. Patient-unique inhalation profiles (inhalation duration: 1, 2, and 3 seconds with associated flows of 100, 60 and 45 L/min), based on individual inspiratory/expiratory scans, were utilized to assess lung deposition. Demographic characteristics and deposition results (percent of delivered dose, %DD) are summarized by descriptive statistics (mean±standard deviation) and box-plot for each airway region by disease and inhalation duration. Results: Twelve asthmatic patients and 12 with COPD were studied [age, years: 46.3±17.3 (asthma); 64.5±8.6 (COPD), FEV1% predicted: 64.2±10.0% (asthma); 42.9±11.1% (COPD)]. Intrathoracic deposition as %DD ranged from 35.3±7.6%-44.5±5.5% for the 400 µg strength across the diseases and inhalation durations. Central deposition was low for both diseases regardless of inspiratory flow rate/inhalation time (range: 2.7±0.9%-4.2±1.4%). Distal deposition was similar for asthma (19.8±4.6%-21.9±5.1%) and COPD (22.2±5.8%-23.3±5.7%) without apparent flow rate effect. Peripheral deposition appeared higher for asthma (14.1±3.6%-19.9±4.0%) than COPD (8.9±2.0%-12.9±2.7%) while for both diseases, deposition was higher with lower flow rates and longer inhalation times. Figure 1 shows deposition as %DD distribution (i.e., box-plot) in each airway region by disease and inhalation duration. Deposition as %DD was similar for the 800 µg strength (data not shown). Conclusions: Tanimilast reached targeted regions in the lungs in asthma and COPD. Peripheral deposition appeared greater in asthma but in both diseases was enhanced by lower inspiratory flow rates with longer inhalation times. This suggests that inhalation strategies may have the potential to improve therapeutic outcomes in obstructive lung diseases.