Management And Prevention Of Chronic Obstructive


Disseminate about the Prevention And Management Of Chronic Obstructive.


Discovery and Development Of Daliresp

DALIRESP is a therapeutic product that contains roflumilast.

Roflumilast can be used as a PDE4 inhibitor.

It is a long-acting and selective inhibitor of enzyme PDE4 (enzyme phosphodiesterase-4).

It was approved by EU in June 2010 to treat severe (chronic obstruction pulmonary disease) COPD. FDA in the US granted approval in March 2011 for COPD relief.

Roflumilast was originally developed as Daliresp in Nycomed, and is now marketed by Forest Laboratories.

Basis of discovery: PDE 4 belongs to the family of 11 enzymes.

These enzymes can catalyze the breakdown of signalling compounds cyclic GMP or cyclic AMP.

PDE 4 (the most important cAMP-metabolizing protein) is found in the immune and inflammatory cells.

PDE4 inhibitors are anti-inflammatory because they inhibit PDE4 (Lipworth (2015)). They also inhibit the release inflammatory mediators and inhibit immune cell activation.

Drug properties

Both roflumilast (and its active metabolite N-oxide) are potent and selective PDE4 inhibitors.

In vitro simulation of human immune cell lines showed that both compounds suppressed inflammatory mediators.

Roflumilast has also been shown to be effective in animal models for airway inflammation.

These models include chronic exposure of cigarette smoke, which reduced the number sputum neutrophils and eosinophils among patients with COPD. Hatzelmann & Schudt (2001)

Chemistry and Other PDE4 Inhibitors

Theophylline is an anti-inflammatory agent that also has immunomodulatory effects. Its bronchodilation dose is lower than the one it produces.

Theophylline is active in multiple tissues and on multiple PDE 4 genes.

This makes theophylline more effective against inflammation. However, it is less therapeutic due to its interactions and adverse effects with other drugs via competition of various cytochrome 450 metabolizing enzymes.

For PDE 4 inhibition, non-xanthine substances were studied.

These non-xanthine-based PDE 4 inhibitors had a higher selectivity towards PDE 4 and thus, there was an improvement in the clinical utility of these non-xanthine PDE 4 antagonists.

The clinical utility of non-xanthine-based compounds, such as benzidines, was demonstrated to be higher.

Roflumilast falls under the benzidine group.

Numerous PDE-4 inhibitors have been developed. However, only roflumilast was able to reach the advanced stages clinical trials.

Cilomilast was more specific towards the PDE4D type; it also displayed gastrointestinal disturbances such as nausea and emesis.

Oglemilast (AWD 12-281, ONO-6126), GSK256066 and SCH900182 were all discontinued due to low efficacy.

In a comprehensive screening program, Roflumilast was found to be a potent PDE 4 inhibitor.

PDE 1 through 11 was used to test the potency and selectivity roflumilast’s metabolite and its selectivity.

Roflumilast achieved clinical success due to its potency and selectivity. It inhibited PDE 4 but not affected PDE1, 2, 3, or 5.

Roflumilast works as a subnanomolar inhibitor of PE 4 and does not affect other PDEs. (Fabbri, 2010).

In vitro and In-vivo efficacy: After synthesizing and evaluating selectivity and specificity of roflumilast it was tested in various in vitro tests.

These assays resulted in decreased apoptosis and release of inflammatory mediators from neutrophils (a reductions in influx leading to a reduction number of neutrophils inside the airways), and decreased expressions of cell surface markers within many cell types (e.g.

adhesion molecules in T cells and decreased release cytokines in many types of cell types (such as interleukin-1b, tumor necrosis factor-alpha, and interleukin-10in macrophages).

It showed effects in vivo such as inhibition cell trafficking and cytokine/chemokine releases from inflammatory cells, including neutrophils.

Roflumilast had a short-term effect on reducing the number of neutrophils in the bronchoalveolar liquid in rats, mice, and guineapigs.

It also reduced the lung parenchymal influx and inflammation in rats after short-term exposure to bacterial lipopolysaccharide and tobacco smoke (Bundschuh et. al., 2001; Lipworth 2015; Hatzelmann & Schudt 2001).

Toxicity tests : A single dose of 100 mg/kg was not fatal in rodents according to toxicology studies.

Repeat dose toxicity tests were performed in mouse (6 month), rat (6 month), hamster (3months), dog (12months), and monkey (42weeks).

NOAEL levels in mice and rats were between 0.2 and 6 mg/kg/day.

These values are higher than the human dose (Karish, Gagnon (2006)

Pharmacokinetics and interactions with drugs: After oral administration, roflumilast can quickly be converted to its active metabolite using cytochrome P450 3A4 or 1A2.

It is obvious that the active metabolite has a similar potency and specificity to roflumilast. It is responsible for the roflumilast’s 90 % efficiency.

Roflumilast, after oral administration, is quickly and completely absorbed. It reaches its plasma concentrations in about 1 hour.

It had a bioavailability of approximately 80 % (Bethke, 2007).

With a median half life of 17 hours, the apparent plasma half-life (t 1/2), of roflumilast ranged from 8 to 31 hours.

Once daily oral administration of roflumilast, steady-state concentrations for the drug reach within 3 – 5 days.

In the dose range of 250 to 1000 ug, the pharmacokinetic profile of Roflumilast was linear and predictable.

The therapeutic dose was determined to be 500 ug, given all the pharmacokinetics of roflumilast.

The pharmacokinetics and metabolism of roflumilast were also examined in patients with renal impairment, hepatic impairment, and 500 ug/day respectively.

There was evidence that roflumilast’s pharmacokinetic, and pharmacodynamic characteristics were altered in patients with renal impairment and hepatic impaired.

For patients with renal impairment and hepatic impairment, dose adjustment was recommended (Hauns, et. al. 2006; Hermann, et. al. 2007).

Drug interaction studies with drugs such as erythromycin (or ketoconazole), digoxin, midazolam and digoxin were performed during its development.

These studies show that there is no interaction with roflumilast.

However, when roflumilast was combined with fluvoxamine or rifampicin, there was an increase and decrease in PDE 4 inhibitor activities (Rabe, et al. 2011, 2011).

Clinical Data

To ensure safety and efficacy, the recommended dosage of roflumilast is 500mg orally once daily.

After Roflimilast was evaluated in numerous randomized, double-blind and placebo-controlled trials (Rabeet al. 2005; Calverleyet al. 2007 ), this dose was decided.

Roflumilast has been evaluated in numerous clinical trials to confirm its effectiveness in COPD.

Roflumilast has been evaluated in patients suffering from COPD, including those with severe or very severe COPD. The post-bronchodilator force expiratory volume per second (forced expiratory volumes in 1 second) was =50%. This is a condition that occurs in patients with chronic cough and/or sputum (chronic asthma) who have had at least one documented disease exacerbation during the past year.

The efficacy of roflumilast in pre-bronchodilatorFEV1 and the incidences of disease complications was demonstrated in this study.

Roflumilast also showed improvements in lung function when compared with the placebo.

As a rescue treatment, corticosteroids, LABAs, and theophylline were administered inhaled.

Daliresp tablets must be taken orally daily.

Eight clinical trials evaluated the efficacy and safety of Daliresp.

These trials were randomised, double-blind, and conducted in a parallel group.

Trials 1 & 2 were placebo controlled and lasted for six months.

Daliresp 250mcg or 500mcg tablets were taken once daily.

These patients had COPD levels between 30 % and 80 %.

Based on no improvement in lung function, 500mcg and 250mcg were chosen.

Trial 3, 4, 5, 6 and 6 were all conducted for one year. They were placebo-controlled trials.

These trials were done in patients suffering from COPD with severity less than 50%.

Calverley and colleagues, 2009). Although exacerbations were not reduced in trial 3 or 4, exploratory studies revealed that COPD exacerbations improved in these patients.

Patients with chronic bronchitis were subject to trials 5 and 6.

These two trials demonstrated improvement in exacerbations. Daliresp also showed safety at 500 mcg. (Fabbri, 2009; Calverley, 2007).

Trials 7 & 8 were carried out for 6 months to add therapy to the bronchodilator.

These trials were done in patients suffering from moderate to severe (40-70% predicted) COPD.

These patients had no history of exacerbations and were not suffering from chronic bronchitis.

Daliresp was found to significantly reduce exacerbations and improve COPD symptoms (Hurst, et al. 2009).

Development – Daliresp is an instant release tablet.

Roflumilast, a Class II active substance, was described based on its biological as well as physicochemical characteristics.

Different excipients for the preparation of coated tablets were examined. Only those excipients that met current compendial monographs were used.

Dissolution studies were conducted on the formula used in clinical studies. The results were comparable to those of in vitro dissolution experiments.

The stability of Daliresp was tested under long term (25degC/60%) or intermediate (30degC/75%) conditions, according to ICH guidelines.

Safety pharmacology studies have been done on the central, autonomic, and cardiovascular systems as well as the renal, respiratory, and gastrointestinal systems.

Roflumilast has cardiovascular side effects that are more acute in dogs than in humans. But, it doesn’t appear to have an effect on the human cardiovascular system.

Daliresp was tested for toxicity at single dose and multiple doses (Gavalda & Roberts, 2013).

The Economic Impact

A higher rate of hospitalisations can be caused by frequent exacerbations due to COPD.

Exacerbations may cause economic problems.

For severe exacerbations, the cost can reach $18,000.

Roflumilast treatment was more expensive than non-roflumilast treatment for severe exacerbations.

However, roflumilast’s total clinical resource utilization is lower than in other treatments.

The treatment cost of roflumilast is comparable to that of other COPD drugs.

It was evident from the cohort studies that the majority of patients who received roflumilast therapy also used combination therapies such as maintenance medications.

Roflumilast was recommended for combination therapy in severely ill patients according to GLOD guidelines.

Roflumilast can cost more for patients who are severely ill (Wan et. al., 2015).


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