Assignment: Management and Prevention of Chronic Obstructive
Assignment: Management and Prevention of Chronic Obstructive
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Discovery and Development of Daliresp
DALIRESP is therapeutic product which contains roflumilast. Roflumilast is a PDE4 inhibitor. It is a selective and long-acting inhibitor of enzyme phosphodiesterase-4 (PDE-4) enzyme. In June 2010, it got approval from EU for severe (chronic obstructive pulmonary disease) COPD associated with chronic bronchitis and in March 2011, it got approval from FDA in US for reducing COPD exacerbations. Roflumilast was developed as Daliresp by Nycomed and marketed by Forest Laboratories.
Basis of discovery: PDE 4 is one of the enzymes of the family of 11 enzymes. These enzymes catalyses the breakdown of signalling molecules cyclic AMP and/or cyclic GMP. PDE 4 is the most significant cAMP-metabolizing enzyme present in the inflammatory and immune cells. PDE4 inhibitors exhibit anti-inflammatory properties by inhibiting PDE4 and inhibit release of inflammatory mediators and also inhibit activation of immune cells (Lipworth, 2015). Assignment: Management and Prevention of Chronic Obstructive
Drug properties :
Both roflumilast and its active metabolite roflumilast N-oxide are potent and selective PDE4 inhibitors. Both these compounds exhibited suppression of inflammatory mediators in vitro by simulation of human immune cells. Roflumilast also exhibited efficacy in animal models of airway inflammation. These models include chronic exposure to cigarette smoke and reduced the number of sputum neutrophils and eosinophils in patients with COPD (Martorana et a., 2005; Hatzelmann & Schudt, 2001).
Chemistry and different PDE 4 inhibitors:
Theophylline exhibits anti-inflammatory and immunomodulatory activity at doses lower than its bronchodilation. However, it exhibits activity on the multiple PDE 4 enzymes in multiple target tissues. Due to this, theophylline has more anti-inflammatory activity; however, it has narrow therapeutic effect due to its adverse effects and interactions with other drugs via competition with various cytochrome (CYP) 450 metabolizing enzymes. Hence, non-xanthine compounds were being studied for the PDE 4 inhibition. These non-xanthine based PDE 4 inhibitors exhibited improved selectivity towards PDE 4; hence there was improved clinical utility of non-xanthine based PDE 4 inhibitors. In non-xanthine based compounds like benzidines proved to be with improved clinical utility. Roflumilast belongs to benzidine group of compounds.
Several PDE 4 inhibitors were developed; however only roflumilast and cilomilast reached to the advanced stages of clinical studies. Cilomilast exhibited greater specificity towards PDE4D subtype; hence it exhibited gastrointestinal disturbances, such as emesis and nausea. Oglemilast, AWD 12–281, ONO-6126, GSK256066, SCH900182, ibudilast, UK-500,001 and tofimilast were discontinued due to lack of efficacy. Roflumilast was identified aa potent PDE 4 inhibitor in comprehensive screening programme. Potency and selectivity of roflumilast and its metabolite were tested in PDE 1 – 11. Roflumilast was advanced in the clinical stages due to high potency and selectivity because it exhibited inhibition of PDE 4 without affecting PDE1, 2, 3 or 5 isoenzymes. Roflumilast is as subnanomolar inhibitor of PE 4 without affecting other PDEs (Fabbri et al., 2010).
In vitro and In vivo efficacy : After synthesis and evaluating specificity and selectivity of roflumilast, it was evaluated in different in vitro assays. These assays exhibited results like decreased apoptosis (result in the clearance of sputum) and release of inflammatory mediators in neutrophils (a reduction in influx resulting in a reduction of neutrophils in the airways), decreased expression of cell surface markers in many cell types (e.g. adhesion molecules in T-cells), and decreased release of cytokines in many cell types (such as tumour necrosis factor alpha, interleukin-1β and interleukin-10 in macrophages) (Lipworth, 2015; Hatzelmann & Schudt, 2001). In vivo it exhibited effects like inhibition of cell trafficking, and cytokine and chemokine release from inflammatory cells such as neutrophils, eosinophils, macrophages and T-cells. Roflumilast exhibited effect in reducing production of neutrophils in bronchoalveolar lavage fluid in guinea pigs, mice or rats after short term exposure of tobacco smoke. It also exhibited effect in reducing accumulation of lung parenchymal influx of inflammatory cells in rats after combined exposure of tobacco smoke and bacterial lipopolysaccharide (Bundschuh et al., 2001; Lipworth, 2015; Hatzelmann & Schudt, 2001).
Toxicity studies : In single dose toxicity studies, 100 mg/kg was found to be non-lethal dose in rodents. Repeat dose toxicity studies were carried out in mouse (6 months), rat (6 months), hamster (3 months), dog (12 months) and monkey (42 weeks). In mouse and rat observed NOAEL were in the range 0.2 to 6 mg/kg/day. These values are much higher than the human dose (Karish and Gagnon, 2006).
Pharmacokinetics and drug interactions: After oral administration, roflumilast is rapidly converted to its active metabolite by cytochrome P450 (CYP) 3A4 and 1A2. It is evident that its metabolite is with equivalent specificity and potency with roflumilast and it is responsible for the 90 % efficacy of the roflumilast. Roflumilast is rapidly and completely absorbed after oral administration and reaches its plasma concentrations (Cmax) at approximately 1 hour. It exhibited approximately 80 % bioavailability (Bethke et al., 2007). Apparent plasma half-life (t½) of roflumilast was found to be 8 to 31 hrs with median half-life of 17 hrs. Steady-state concentration for roflumilast reaches within 3 – 4 days after once daily oral administration. Pharmacokinetic profile of roflumilast was found to be linear and predictable in the dose range of 250–1000 µg. By considering all the pharmacokinetic and pharmacodynamic properties of roflumilast, 500 µg once daily was decided as the therapeutic dose.
Pharmacokinetics of roflumilast was also evaluated in patients with renal impairment and hepatic impairment at doses of 500 µg and 250 µg respectively. It was evident that in both renal and hepatic impairment patients, there was alteration in pharmacokinetic and pharmacodynamic properties of roflumilast. Hence, dose adjustment for roflumilast was suggested for patients with renal and hepatic impairment (Hauns et al., 2006; Hermann et al., 2007). During its development phase, drug interaction studies were conducted with various drugs like erythromycin, ketoconazole, midazolam, digoxin and Maalox®, an antacid containing magnesium hydroxide and aluminium hydroxide. From these studies, it is evident that there is no interaction of these drugs with roflumilast. However, consumption of roflumilast with rifampicin and fluvoxamine, there was increase and decrease in the PDE 4 inhibitor activity respectively (Rabe et al., 2011).
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Clinical data :
500 μg orally once daily was decided as the dose of roflumilast for its safety and efficacy. This dose was decided after evaluating Roflimilast in number of randomized, double-blind, placebo-controlled trials (Rabe et al., 2005; Calverley et al., 2007 ).
Roflumilast was evaluated in numerous clinical trials for confirming efficacy in COPD. Roflumilast was evaluated in patients with severe to very severe COPD (post-bronchodilator FEV1 (forced expiratory volume in 1 second) ≤50% of the predicted value based on gender, age and height controls) associated with chronic cough and sputum (chronic bronchitis), with at least one documented disease exacerbation in the previous year. In this study, roflumilast exhibited efficacy in pre-bronchodilator FEV1 and occurences of disease exacerbations. Roflumilast also exhibited improvement in lung function …