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Background: The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy., Methods: In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1:1:1 to 4 weeks' treatment with ROF 250 µg once daily (OD), 500 µg every other day (EOD), or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment., Results: Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations (odds ratio [OR] 0.66 [95% CI 0.47-0.93], p =0.017) and lower rates of AEs of interest such as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (OR 0.63 [95% CI 0.47-0.83], p =0.001) compared with those in the 500 µg OD group. Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD, the difference was not significant (OR 0.76, p =0.114, and OR 0.78, p =0.091, respectively) compared with ROF 500 µg OD., Conclusion: A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD resulted in reduced treatment discontinuation and improved tolerability., Competing Interests: Disclosure NB was employed by Takeda Development Centre Europe Ltd, London, UK. The authors report no other conflicts of interest in this work.

Background: Preclinical evaluation of new chemical entities (NCEs) designed to be administered by inhalation route requires lung administration to rodents, especially in the discovery phase. Different administration methods have been used until now, but more efforts are required to obtain controlled and reproducible lung deposition when only small amounts of neat powder material are available., Methods: The PreciseInhale platform used in the present study enables well-controlled powder aerosol exposures with only small amounts of micronized neat material, providing data on inhalation pharmacokinetic (PK) of NCEs at a very early stage. The DustGun aerosol technology uses compressed air to generate a respirable aerosol from milligram-amounts of powder that is delivered to one animal at a time. The new methodology was used to investigate the inhalation PK and lung retention in the rat of the novel Chiesi PDE4 inhibitor CHF6001 in three exposure models of the PreciseInhale platform: nose-only, intratracheally intubated rat, and the isolated, ventilated, and perfused rat lung. Results were compared with data from two other pulmonary delivery systems commonly used in preclinical studies: liquid instillation and powder insufflation., Results: Administration of micronized CHF6001 using the PreciseInhale system yielded lung exposures in the same range as the other tested devices, but the reproducibility in lung deposition was improved. The initial amount of CHF6001 in lungs at the first sampling time point was close to the predetermined target dose. Tracheal deposition with PreciseInhale (0.36 ± 0.22 μg) was significantly less than with other tested delivery systems: PennCentury (23.7 ± 3.2 μg) and Airjet (25.6 ± 7.2 μg)., Conclusions: The PreciseInhale platform enabled the administration of CHF6001 powder with good accuracy and reproducibility, with low tracheal deposition. The new platform can be used at an early discovery stage to obtain inhalatory PK data for respirable aerosols of neat NCE powder without excipients and with minimal use of dry powder formulation work.

Background: Roflumilast, a once-daily, selective phosphodiesterase-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. The RE(2)SPOND study is examining whether roflumilast, when added to an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) fixed-dose combination (FDC), further reduces exacerbations. The methodology is described herein., Methods: In this Phase IV, multicenter, double-blind, placebo-controlled, parallel-group trial, participants were randomized 1:1 (stratified by long-acting muscarinic antagonist use) to receive roflumilast or placebo, plus ICS/LABA FDC, for 52 weeks. Eligible participants had severe COPD associated with chronic bronchitis, had two or more moderate-severe exacerbations within 12 months, and were receiving ICS/LABA FDC for ≥3 months. The primary efficacy measure is the rate of moderate or severe COPD exacerbations per participant per year. The secondary efficacy outcomes include mean change in prebronchodilator forced expiratory volume in 1 second (FEV1) over 52 weeks, rate of severe exacerbations, and rate of moderate, severe, or antibiotic-treated exacerbations. Additional assessments include spirometry, rescue medication use, the COPD assessment test, daily symptoms using the EXACT-Respiratory symptoms (E-RS) questionnaire, all-cause and COPD-related hospitalizations, and safety and pharmacokinetic measures., Results: Across 17 countries, 2,354 participants were randomized from September 2011 to October 2014. Enrollment goal was met in October 2014, and study completion occurred in June 2016., Conclusion: This study will further characterize the effects of roflumilast added to ICS/LABA on exacerbation rates, lung function, and health of severe-very severe COPD participants at risk of further exacerbations. The results will determine the clinical benefits of roflumilast combined with standard-of-care inhaled COPD treatment.

A novel nanovesicle carrier, phosphatiosomes, was developed to enhance the targeting efficiency of phosphodiesterase 4 (PDE4) inhibitor to the lungs for treating acute lung injury (ALI) by intravenous administration. Phosphatiosomes were the basis of a niosomal system containing phosphatidylcholine (PC) and distearoylphosphatidylethanolamine polyethylene glycol (DSPE-PEG). Rolipram was used as the model drug loaded in the phosphatiosomes. Bioimaging, biodistribution, activated neutrophil inhibition, and ALI treatment were performed to evaluate the feasibility of phosphatiosomes as the lung-targeting carriers. An encapsulation percentage of >90% was achieved for rolipram-loaded nanovesicles. The vesicle size and zeta potential of the phosphatiosomes were 154 nm and -34 mV, respectively. Real-time imaging in rats showed a delayed and lower uptake of phosphatiosomes by the liver and spleen. Ex vivo bioimaging demonstrated a high accumulation of phosphatiosomes in the lungs. In vivo biodistribution exhibited increased lung accumulation and reduced brain penetration of rolipram in phosphatiosomes relative to the control solution. Phosphatiosomes improved the lungs/brain ratio of the drug by more than 7-fold. Interaction with pulmonary lipoprotein surfactants and the subsequent aggregation may be the mechanisms for facilitating lung targeting by phosphatiosomes. Rolipram could continue to inhibit active neutrophils after inclusion in the nanovesicles by suppressing O2(-) generation and elevating cAMP. Phosphatiosomes significantly alleviated ALI in mice as revealed by examining their pulmonary appearance, edema, myeloperoxidase (MPO) activity, and histopathology. This study highlights the potential of nanovesicles to deliver the drug for targeting the lungs and attenuating nervous system side effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Roflumilast is a newly approved phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of exacerbations., Objective: The objective of this article is to review the pharmacology, clinical efficacy, and tolerability of roflumilast in the treatment of COPD., Methods: Articles were identified using MEDLINE (1966-August 1, 2011) and EMBASE (1947-August 1, 2011). Searches were conducted using the terms roflumilast and COPD. Included in the search were all English-language clinical trials that were randomized, had durations of >6 weeks, and studied the effects of roflumilast on the forced expiratory volume in 1 second (FEV(1)) or rates of exacerbations in patients with COPD. Abstracts from the annual meetings of the American Thoracic Society, American College of Chest Physicians, and European Respiratory Society were also searched to identify relevant publications. In addition, all pertinent studies evaluating the pharmacokinetics and pharmacodynamics of roflumilast were included., Results: A total of 6 clinical trials (4 publications) evaluating the efficacy of roflumilast were identified and included. For the treatment of COPD, roflumilast was associated with a significant improvement in lung function (increase in FEV(1) of 36-88 mL) when compared with placebo. Roflumilast also reduced the rate of exacerbations in subsets of patients with chronic cough and a history of exacerbations. Overall, health-related quality of life was not significantly affected. Adverse effects were common in clinical trials, with 9% to 16% of patients discontinuing therapy as a result. The most frequently reported adverse effects were gastrointestinal issues, headache, and weight loss. Suicide-related adverse effects have occurred in 5 patients receiving roflumilast and 1 patient receiving placebo., Conclusion: Roflumilast significantly improved FEV(1) in clinical trials but had inconsistent reductions in the rates of exacerbations. Comparative studies with recommended therapies for COPD, particularly inhaled corticosteroids, are needed to better assess the role of roflumilast in the management of COPD., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Roflumilast is a new phosphodiesterase 4 inhibitor that has recently completed Phase III trials for the treatment of chronic obstructive pulmonary disease (COPD). Preclinical studies have shown that roflumilast targets inflammatory processes in COPD, with beneficial effects on tobacco-induced lung inflammation, lung fibrosis and remodeling, mucociliary malfunction and oxidative stress. Two recent, 1-year Phase III trials in COPD have shown that roflumilast reduces exacerbations and improves lung function in patients with COPD who have symptoms of chronic bronchitis and a history of exacerbations. Two other 6-month Phase III trials have demonstrated the beneficial effects of roflumilast in patients already receiving treatment with the long-acting β-agonist salmeterol or the long-acting muscarinic antagonist tiotropium. This article reviews the pharmacology, pharmacokinetics and preclinical pharmacology of roflumilast, the clinical studies supporting its use in COPD and its side-effect profile.