Roflumilast In Chronic Obstructive Pulmonary Disease Research Articles

The Dosing Strategy to Improve Adherence to Roflumilast in Treatment for Chronic Obstructive Lung Disease: A Systemic Review and Meta-Analysis.

The clinical efficacy of roflumilast, an oral phosphodiesterase-4 inhibitor, has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD). However, roflumilast has shown frequent adverse drug reactions (ADRs). This study was performed to investigate the dosing strategy that will improve adherence to roflumilast in COPD. We conducted a systematic review and meta-analysis using PubMed, Embase, and Cochrane Central Register. The dosing strategy for roflumilast was classified into a dose-escalation group and a low-dose group. We investigated clinical outcomes according to dosing strategy. Five clinical trials involving 2424 patients were included. Both the dose-escalation and the low-dose groups showed a decrease in discontinuation rate compared to the standard dosing group for roflumilast (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.67-0.97; P = 0.02 and RR, 0.62; 95% CI, 0.48-0.80; P < 0.01, respectively). In the two strategies, the pooled proportions of discontinuation were 27.9% and 11.7%, respectively. Although the pooled proportion of any ADR was not statistically decreased in the two strategies, diarrhea was significantly reduced in the low-dose group compared to the standard group (RR, 0.58; 95% CI, 0.42-0.82; P < 0.01). The pooled incidence of acute exacerbations was similar between the low-dose and the standard groups (22.9% and 20.1%, respectively; P = 0.27). Our findings show that the two alternative dosing strategies might have the benefit of improving adherence to roflumilast in COPD. Further large-scale trials are required to support our findings.

Impact of Phosphodiesterase 4 Inhibition on the Operational Efficacy, Response Maxima, and Kinetics of Indacaterol-Induced Gene Expression Changes in BEAS-2B Airway Epithelial Cells: A Global Transcriptomic Analysis.

The effects of phosphodiesterase (PDE) 4 inhibitors on gene expression changes in BEAS-2B human airway epithelial cells are reported and discussed in relation to the mechanism(s) of action of roflumilast in chronic obstructive pulmonary disease (COPD). Microarray-based gene expression profiling failed to identify mRNA transcripts that were differentially regulated by the PDE4 inhibitor 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) after 1, 2, 6, or 18 hours of exposure. However, real-time polymerase chain reaction analysis revealed that GSK 256066 was a weak stimulus, and the negative microarray results reflected low statistical power due to small sample sizes. Furthermore, GSK 256066, roflumilast, and its biologically active metabolite roflumilast N-oxide generally potentiated gene expression changes produced by the long-acting β 2-adrenoceptor agonists (LABAs) salmeterol, indacaterol, and formoterol. Many of these genes encode proteins with antiviral, anti-inflammatory, and antibacterial activities that could contribute to the clinical efficacy of roflumilast in COPD. RNA-sequencing experiments established that the sensitivity of genes to salmeterol varied by ∼7.5-fold. Consequently, the degree to which a PDE4 inhibitor potentiated the effect of a given concentration of LABA was gene-dependent. Operational model fitting of concentration-response curve data from cells subjected to fractional, β 2-adrenoceptor inactivation determined that PDE4 inhibition increased the potency and doubled the efficacy of LABAs. Thus, adding roflumilast to standard triple therapy, as COPD guidelines recommend, may have clinical relevance, especially in target tissues where LABAs behave as partial agonists. Collectively, these results suggest that the genomic impact of roflumilast, including its ability to augment LABA-induced gene expression changes, may contribute to its therapeutic activity in COPD.

Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomised, placebo-controlled trial

The clinical effects of roflumilast, a selective phosphodiesterase-4 inhibitor, are well established, but little is known about the anti-inflammatory mechanisms underlying the drug's efficacy. The aim of the ROflumilast Biopsy European Research Trial (ROBERT) was to assess the anti-inflammatory effects of roflumilast on bronchial mucosal inflammation in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis. ROBERT was a randomised, double-blind, placebo-controlled trial done at 18 sites in five countries. Eligible patients were aged 40-80 years, had COPD, and had had a chronic productive cough for 3 months in each of the two previous years. Patients also had to have a post-bronchodilator predicted FEV1 30-80% and a post-bronchodilator FEV1/forced vital capacity ratio of 70% or less. Patients entered a 6-week run-in period before being randomly assigned (1:1) via a computerised central randomisation system to roflumilast 500 μg once daily or placebo for 16 weeks, in addition to bronchodilator therapy (inhaled corticosteroids were not permitted). Randomisation was stratified by concomitant use of long-acting β agonist. Both participants and investigators were masked to group assignment. Roflumilast and placebo were supplied as identical yellow, triangular tablets. Airway inflammation was assessed by quantification of inflammatory cells in bronchial biopsy samples and induced sputum samples. The primary endpoint was the change in the number of CD8 inflammatory cells in bronchial biopsy submucosa from randomisation to week 16 in the intention-to-treat population. Changes in cell counts of additional inflammatory markers, including eosinophils, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, number NCT01509677, and is closed to new participants, with follow-up completed. Between Jan 4, 2012, and Feb 11, 2016, 158 patients were randomly assigned: 79 to the roflumilast group, and 79 to the placebo group. At week 16, the change in the number of CD8 cells in the bronchial submucosa did not differ significantly between the roflumilast and placebo groups (treatment ratio 1·03 [95% CI 0·82-1·30]; p=0·79). However, compared with placebo, roflumilast was associated with a significant reduction in eosinophils in bronchial biopsy samples at week 16 (treatment ratio 0·53 [95% CI 0·34-0·82]; p=0·0046). Significant reductions in both absolute (p=0·0042) and differential (p=0·0086) eosinophil cell counts in induced sputum were also noted with roflumilast compared with placebo, but peripheral blood eosinophil counts were not significantly affected. We noted no other significant effects of roflumilast on bronchial mucosal inflammatory cells. The most common (ie, occurring in >5% patients) moderate adverse events were worsening of COPD (three [4%] patients in the roflumilast group vs seven [9%] in the placebo group), cough (six [8%] vs four [5%]), diarrhoea (four [5%] vs three [4%]), and nasopharyngitis (three [4%] vs five [6%]). Severe adverse events included worsening of COPD, which occurred in four (5%) patients in the roflumilast group and two (3%) in the placebo group. No deaths occurred during the study. Serious adverse events occurred in eight (10%) patients in the roflumilast group and five (6%) in the placebo group. 16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo. However, we noted significant reductions in eosinophil cell counts in bronchial biopsy samples and induced sputum, generating the hypothesis that the effect of roflumilast in COPD could be mediated by an effect on lung eosinophils. Takeda and AstraZeneca.

Risk factors for the discontinuation of roflumilast in patients with chronic obstructive pulmonary disease.

IntroductionRoflumilast is a phosphodiesterase-4 inhibitor, which can decrease exacerbation in patients with chronic obstructive pulmonary disease (COPD). However, adverse effects are a major barrier to medication use, and little is known regarding the risk factors for discontinuation of roflumilast in COPD patients.MethodA search of the clinical databases identified all patients who were prescribed roflumilast between December 2012 and April 2015 in the four hospitals of The Catholic University of Korea, Korea. The study subjects were limited to patients who had taken 500 μg of roflumilast. We studied the factors associated with drug discontinuation and drug adverse events by univariate and multivariate analyses.ResultsAmong 154 eligible patients, 54 (35.1%) discontinued their roflumilast prescription. Most patients were elderly, male, current or former smokers, and had moderate-to-severe airflow limitation. Low–body mass index (BMI) patients were more likely to undergo drug discontinuation (1-unit decrease in BMI: odds ratio [OR] =1.165, p=0.006; BMI <23 kg/m2: OR =2.960, p=0.004). Fifty-five patients (35.7%) had adverse events. Loss of appetite, diarrhea, nausea, headache, and weight loss were the most frequent adverse events. Low-BMI patients were more likely to experience adverse events (1-unit decrease in BMI: OR =1.151, p=0.010; BMI <23 kg/m2: OR =2.644, p=0.009).ConclusionsThe patient discontinuation and adverse events rates in this study were higher than in previous randomized controlled studies. Discontinuation of roflumilast in ethnic Koreans is more likely to occur in low-BMI patients. In a clinical setting, low-BMI patients can more easily discontinue roflumilast; clinicians should, therefore, provide greater care for these patients.

The use of roflumilast in COPD: a review

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Chronic inflammation and exacerbations play a central role in the progression of the disease. Currently, treatment options for COPD have been shown to improve the progressive decline in lung-function and/or decrease mortality rates. Roflumilast, a phosphodiesterase- 4 inhibitor, is an anti-inflammatory drug which has been licensed as an add-on therapy for COPD patients with forced expiratory volume in the first second &amp;lt;50% and frequent exacerbations. Clinical trials have demonstrated that roflumilast improves lung function and reduces exacerbation frequency. Roflumilast has a mechanism of action which allows it to obtain a significant additive effect to current therapeutic options for COPD patients. It is generally well tolerated, although the most common adverse effects include diarrhea, nausea, weight loss, and headache. This review article provides an overview of the positive effects of roflumilast on lung function, exacerbation frequency and glucose metabolism, and its interaction with concomitant inhaled treatments.

Roflumilast for the treatment of respiratory disease: review of the Phase II and III trials

Roflumilast (Daxas® [EU], Daliresp® [USA]) is the first phosphodiesterase 4 inhibitor approved in Europe to be used in severe chronic obstructive pulmonary disease (COPD). Its preclinical evaluation streamed its subsequent clinical development towards COPD based on the prominent anti-inflammatory activities demonstrated in various preclinical models of COPD. Its clinical development was based mainly on Phase III studies initially performed in COPD patients with various stages of disease severity and then focused on severe COPD patients with chronic bronchitis. On both a short- and long-term basis, roflumilast was demonstrated to reduce the incidence of moderate to severe COPD exacerbations and to improve lung function. This article discusses the clinical relevance of the data coming from Phase II and III studies and raises some issues related to the use of roflumilast in COPD.

The use of roflumilast in COPD: a primary care perspective

Therapeutic interventions in chronic obstructive pulmonary disease (COPD) shown to reduce exacerbations include smoking cessation, vaccination and appropriate pharmacological therapy. Long-acting bronchodilators are the cornerstone of COPD pharmacotherapy, whereas inhaled corticosteroids and mucolytics have shown benefit in subgroups of patients. Despite management with existing therapies, clinical trials confirm the persistent nature of exacerbations throughout the course of the disease. Roflumilast - a phosphodiesterase-4 (PDE4) inhibitor - received European Marketing Approval in 2010 and represents a new class of drug in the management of COPD. Through selective inhibition of the PDE4 enzyme, roflumilast prevents the breakdown of cyclic AMP, which plays an important role in regulating inflammatory cell activity. Early trials in patients with a forced expiratory volume in one second (FEV1) less than 50% predicted suggest that roflumilast offers sustained and significant improvement in lung function and a reduction in exacerbations compared with placebo, irrespective of concomitant bronchodilator therapy. Common adverse events include headache, diarrhoea and weight loss, with the majority occurring at the beginning of treatment, being transient and not leading to sequelae. Serious adverse events tended to be low across all studies. Roflumilast is currently licensed in Europe, and is indicated as maintenance treatment in severe COPD (i.e. in patients with post-bronchodilator FEV1 <50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as an add-on to bronchodilator treatment. Clear identification of patients eligible for roflumilast will require improved characterisation and phenotyping of patients in primary care, including lung function measurement, accurate health status classification, and recording of chronic cough and regular sputum production.

Roflumilast in chronic obstructive pulmonary disease: evidence from large trials

Importance of the field: Chronic inflammation plays a central role in chronic obstructive pulmonary disease (COPD). Suppression of the inflammatory response is a logical approach to the treatment of COPD. Corticosteroids are highly effective as an anti-inflammatory treatment, but patients with COPD are poorly responsive to these drugs. The phosphodiesterase (PDE)-4 isoenzyme is a major therapeutic target in COPD because its inhibition increases intracellular cAMP concentrations, which ultimately results in reduction of cellular inflammatory activity. At present roflumilast is the most advanced PDE-4 inhibitor undergoing clinical trials for COPD.Areas covered in this review: In this paper, we describe the importance of roflumilast as an anti-inflammatory drug and critically review the results of four large trials with roflumilast in COPD (NCT00297102, NCT00297115, NCT00313209, NCT00424268).What the reader will gain: An unbiased description of trials that have explored the therapeutic effects of roflumilast in COPD.Take home message: At the moment, roflumilast should only be considered as a second-line treatment, and the exact indication remains to be determined. Apparently, it should be reserved for patients who have frequent exacerbations despite treatment with inhaled bronchodilators. However, considering the high risk of adverse events induced by this drug, the published evidence seems to indicate limiting its use to the treatment of patients suffering from very severe COPD.

Roflumilast for COPD

Patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis have a reduction in lung function and a higher risk of suffering exacerbations, which result in a deterioration in their quality of life, an accelerated progression of the disease and a greater mortality. COPD is currently considered an inflammatory disease involving airways and lung parenchyma. The symptoms that are typical of chronic bronchitis (chronic cough and sputum production) are markers of underlying inflammation, characteristic of COPD. Roflumilast, an antiinflammatory drug that belongs to the new therapeutic class of phosphodiesterase PDE4 inhibitors, is the first drug developed for the treatment of a specific phenotype of COPD (COPD associated with chronic bronchitis). The results of clinical trials indicated that in patients with COPD associated with chronic bronchitis and a history of exacerbations, roflumilast improves lung function and reduces the frequency of exacerbations that require medical interventions. This effect remained when it was added to a regular treatment with long-acting bronchodilators such as tiotropium or long-acting β₂-adrenoceptor agonists (LABAs) such as salmeterol. Roflumilast has been shown to be generally well tolerated. Side effects were typically mild to moderate and included diarrhea, nausea, weight decrease and headache. Gastrointestinal side effects mainly occurred within the first weeks of therapy and mostly resolved on continued treatment.

Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma

Background: Roflumilast is a selective phosphodiesterase-4 inhibitor with a broad range of anti-inflammatory actions. Studies in asthma and chronic obstructive pulmonary disease (COPD) have demonstrated that it can improve lung function and reduce inflammation. Objective: To review the clinical data on roflumilast in COPD and asthma. Methods: A PubMed search using the term roflumilast was used to identify articles, and the bibliographies of the identified articles were reviewed to identify other relevant reports. All roflumilast abstracts from the 2006 and 2007 International Meetings of the American College of Chest Physicians, American Thoracic Society and European Respiratory Society were also reviewed. Results/conclusion: The preliminary studies of roflumilast in COPD and asthma have only shown modest clinical benefits and may be associated with gastrointestinal side effects. Further studies are required to clarify the role of roflumilast in the management of COPD and asthma.