Roflumilast for the treatment of chronic obstructive pulmonary disease

Expert Review of Respiratory Medicine

Volumn 4, Issue 5, 2010, Pages 543-555

  Rabe, Klaus F ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

anti inflammatory; chronic obstructive pulmonary disease; cough and sputum; exacerbations; lung function; phosphodiesterase 4 inhibitor; roflumilast

Indexed keywords

RESPIRATORY TRACT AGENT; ROFLUMILAST; SALMETEROL; TIOTROPIUM BROMIDE; TOBACCO SMOKE;

CHRONIC BRONCHITIS; CHRONIC OBSTRUCTIVE LUNG DISEASE; DIARRHEA; DISEASE EXACERBATION; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; FORCED EXPIRATORY VOLUME; HEADACHE; HUMAN; INSOMNIA; LUNG FIBROSIS; LUNG FUNCTION; NAUSEA; NONHUMAN; OXIDATIVE STRESS; PNEUMONIA; QUALITY OF LIFE; REVIEW; SIDE EFFECT; TREATMENT DURATION; WEIGHT REDUCTION;

EID: 77958005826     PISSN: 17476348     EISSN: 17476356     Source Type: Journal    
DOI: 10.1586/ers.10.56     Document Type: Review

References (86)

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (updated 2009). National Heart, Lung and Blood Institute, Bethesda, MD, USA (2009). • Evidence-based guidelines for the management of chronic obstructive pulmonary disease (COPD).
2. Celli BR, Thomas NE, Anderson JA et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: Results from the TORCH study. Am. J. Respir. Crit. Care Med. 178(4), 332-338 (2008).
3. Barnes PJ, Stockley RA. COPD: Current therapeutic interventions and future approaches. Eur. Respir. J. 25(6), 1084-1106 (2005).
4. Salpeter SR, Buckley NS. Systematic review of clinical outcomes in chronic obstructive pulmonary disease: B-agonist use compared with anticholinergics and inhaled corticosteroids. Clin. Rev. Allergy Immunol. 31(2-3), 219-230 (2006).
5. Hawkins NM, Jhund PS, Simpson CR et al. Primary care burden and treatment of patients with heart failure and chronic obstructive pulmonary disease in Scotland. Eur. J. Heart Fail. 12(1), 17-24 (2010).
6. Hawkins NM, Wang D, Petrie MC et al. Baseline characteristics and outcomes of patients with heart failure receiving bronchodilators in the CHARM programme. Eur. J. Heart Fail. 12(6), 557-565 (2010).
7. Tashkin DP, Celli B, Senn S et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N. Engl. J. Med. 359(15), 1543-1554 (2008).
8. Nickels TJ, Schwartz AD, Blevins DE, Drummond JT, Reed GW, Wilson DF. Effect of theophylline and aminophylline on transmitter release at the mammalian neuromuscular junction is not mediated by cAMP. Clin. Exp. Pharmacol. Physiol. 33(5-6), 465-470 (2006).
9. Fukuhara S, Nishimura M, Nordyke RJ, Zaher CA, Peabody JW. Patterns of care for COPD by Japanese physicians. Respirology 10(3), 341-348 (2005).
10. Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ. Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137(6), 1338-1344 (2010).
11. Barnes N, Snape S, Fox JC et al. Effects of low dose inhaled theophylline (ADC4022) co-administered with budesonide on inflammatory markers and lung function in patients with COPD. Am. J. Respir. Crit. Care Med. 181, A4470 (2010).
12. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: Results from the lung health study. Am. J. Respir. Crit. Care Med. 164(3), 358-364 (2001).
13. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 57(10), 847-852 (2002).
14. Soler-Cataluna JJ, Martinez-Garcia MA, Roman SP, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 60(11), 925-931 (2005).
15. Kessler R, Stahl E, Vogelmeier C et al. Patient understanding, detection, and experience of COPD exacerbations: An observational, interview-based study. Chest 130(1), 133-142 (2006).
16. Barnette MS. Phosphodiesterase 4 (PDE4) inhibitors in asthma and chronic obstructive pulmonary disease (COPD). Prog. Drug Res. 53, 193-229 (1999).
17. Rennard SI, Knobil K, Rabe KF et al. The efficacy and safety of cilomilast in COPD. Drugs 68 (Suppl. 2), 3-57 (2008).
18. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials. Lancet 374(9691), 685-694 (2009). •• Overview of two 1-year, randomized clinical trials showing the beneficial effects of roflumilast on lung function and exacerbations in symptomatic COPD.
19. Fabbri LM, Calverley PM, Izquierdo-Alonso JL et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: Two randomised clinical trials. Lancet 374(9691), 695-703 (2009). •• Two 6-month, randomized clinical trials reporting the efficacy of roflumilast when coadministered with long-acting bronchodilators in moderate-to-severe COPD.
20. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J. Pharmacol. Exp. Ther. 297(1), 267-279 (2001).
21. Giembycz MA. An update and appraisal of the cilomilast Phase III clinical development programme for chronic obstructive pulmonary disease. Br. J. Clin. Pharmacol. 62(2), 138-152 (2006).
22. Pryzwansky KB, Madden VJ. Type 4A cAMP-specific phosphodiesterase is stored in granules of human neutrophils and eosinophils. Cell Tissue Res. 312(3), 301-311 (2003).
23. Giembycz MA. Development status of second generation PDE4 inhibitors for asthma and COPD: The story so far. Monaldi Arch. Chest Dis. 57(1), 48-64 (2002).
24. Giembycz MA. 4D or not 4D - the emetogenic basis of PDE4 inhibitors uncovered? Trends Pharmacol. Sci. 23(12), 548 (2002).
25. Lehnart SE, Marks AR. Phosphodiesterase 4D and heart failure: A cautionary tale. Expert Opin. Ther. Targets 10(5), 677-688 (2006).
26. Carnini C, Caruso P, Bassani F et al. Cigarette smoke-induced inflammatory and oxidative response in mice and pharmacological intervention studies involving compounds with different mechanism of action. Am. J. Respir. Crit. Care Med. 179, A2025 (2009).
27. Fitzgerald MF. Efficacy of the PDE4 inhibitor, Bay 19-8004, in a smoke-induced model of pulmonary inflammation in the guinea pig. Am. J. Respir. Crit. Care Med. 163, A905 (2001).
28. Fitzgerald MF, Spicer D, McAulay AE, Wollin L, Beume R. Roflumilast but not methylprednisolone inhibited cigarette smoke-induced pulmonary inflammation in guinea pigs. Eur. Respir. J. Suppl. 663S, P3850 (2006).
29. Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am. J. Respir. Crit. Care Med. 172, 848-853 (2005).
30. Stevenson CS, Wan WYH, Mok J, Pearce W, Morris A, Kinnear G. Does the impact of anti-inflammatory compounds in acute smoking mouse models predict therapeutic efficacy in more chronic models. Am. J. Respir. Crit. Care Med. 179, A2224 (2009).
31. Weidenbach A, Braun C, Schwoebel F, Beume R, Marx D. Therapeutic effects of various PDE4 inhibitors on cigarette smoke-induced pulmonary neutrophilia in mice. Am. J. Respir. Crit. Care Med. 178, A651 (2008).
32. Cortijo J, Iranzo A, Milara X et al. Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. Br. J. Pharmacol. 156(3), 534-544 (2009).
33. Mata M, Sarria B, Buenestado A, Cortijo J, Cerda M, Morcillo EJ. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax 60(2), 144-152 (2005).
34. Milara J, Cortijo J, Armengot M, Banuls P, Gabarda E, Morcillo E. Effect of roflumilast, a PDE4 inhibitor on ciliary beat frequency in human nasal epithelial cells. Eur. Respir. J. Suppl. 639S, P3651 (2008).
35. Wohlsen A, Wollin L, Marx D, Beume R. Effect of roflumilast and other cAMP elevating agents on airway beat ciliary frequency in proximal and distal airways in rat precision cut lung slices. Presented at: 5th International Multidisciplinary Conference on Chronic Obstructive Pulmonary Disease (COPD5). Birmingham, UK, 28-30 June 2006 (Poster P25).
36. Muzaffar S, Shukla N, Angelini GD, Jeremy JY. Roflumilast N-oxide inhibits NADPH oxidase expression and activity in human pulmonary artery smooth muscle cells. Proc. Br. Pharmacol. Soc. 6, 027P (2008).
37. Izikki M, Raffestin B, Klar J et al. Effects of roflumilast, a phosphodiesterase-4 inhibitor, on hypoxia- and monocrotaline-induced pulmonary hypertension in rats. J. Pharmacol. Exp. Ther. 330(1), 54-62 (2009).
38. Hardaker EL, Freeman MS, Dale N et al. Characterisation of a model that mimicks aspects of the hyper-inflammatory response observed during an acute exacerbation of COPD. Am. J. Respir. Crit. Care Med. 179, A5351 (2009).
39. Ge XN, Chu HW, Minor MN, Case SR, Bosch DG, Martin RJ. Roflumilast increases Clara cell secretory protein in cigarette smoke-exposed mice. COPD 6(3), 185-191 (2009).
40. Guleria R, Singh TR, Sinha S, Padhy K, Gupta K, Pande JN. Effect of single inhalation of a salbutamol, ipratropium bromide and beclomethasone on mucociliary clearance in patients with chronic obstructive airway disease. Indian J. Chest Dis. Allied Sci. 45(4), 241-246 (2003).
41. Agusti AG. COPD, a multicomponent disease: Implications for management. Respir. Med. 99(6), 670-682 (2005). • Overview of COPD as a systemic disease.
42. Hogg JC, Chu F, Utokaparch S et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350(26), 2645-2653 (2004). • Study detailing the evolution of the pathological effects of airway obstruction in COPD.
43. Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am. J. Respir. Crit. Care Med. 153(5), 1530-1535 (1996).
44. Chung KF. The role of airway smooth muscle in the pathogenesis of airway wall remodeling in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2(4), 347-354 (2005).
45. Rahman I. Oxidative stress in pathogenesis of chronic obstructive pulmonary disease: Cellular and molecular mechanisms. Cell Biochem. Biophys. 43(1), 167-188 (2005).
46. Bowler RP, Barnes PJ, Crapo JD. The role of oxidative stress in chronic obstructive pulmonary disease. COPD 1(2), 255-277 (2004).
47. Marwick JA, Ito K, Adcock IM, Kirkham PA. Oxidative stress and steroid resistance in asthma and COPD: Pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin. Ther. Targets 11(6), 745-755 (2007).
48. MacNee W. Oxidants/antioxidants and COPD. Chest 117(5 Suppl. 1), 303S-317S (2000).
49. Sanz MJ, Cortijo J, Taha MA et al. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br. J. Pharmacol. 152(4), 481-492 (2007).
50. Grootendorst DC, Gauw SA, Verhoosel RM et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62(12), 1081-1087 (2007). • Study reporting the anti-inflammatory activity of roflumilast in COPD as demonstrated by reductions in neutrophil and eosinophil numbers in induced sputum.
51. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur. Respir. J. 32(5), 1371-1385 (2008).
52. Santos S, Peinado VI, Ramirez J et al. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur. Respir. J. 19(4), 632-638 (2002).
53. Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J. Pharmacol. Exp. Ther. 297(1), 280-290 (2001).
54. Engelstatter R, Wingertzahn M, Schmid-Wirlitsch C, Bredenbrocker D, Leichtl S, Wurst W. Roflumilast, an oral once-daily phosphodiesterase 4 (PDE4) inhibitor does not exhibit bronchodilator activity. Ann. Allergy Asthma Immunol. 94, 169 (2005).
55. Wollin L, Bundschuh DS, Wohlsen A, Marx D, Beume R. Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors. Pulm. Pharmacol. Ther. 19(5), 343-352 (2006).
56. David M, Zech K, Seiberling M, Weimar C, Bethke TD. Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high oral bioavailability. J. Allergy Clin. Immunol. 113, S220-S221 (2004).
57. Hauns B, Hermann R, Hunnemeyer A et al. Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects. J. Clin. Pharmacol. 46(10), 1146-1153 (2006). (Pubitemid 44387414)
58. Bethke TD, Böhmer GM, Hermann R et al. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J. Clin. Pharmacol. 47(1), 26-36 (2007).
59. Bethke TD, Giessmann T, Westphal K et al. Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects. Int. J. Clin. Pharmacol. Ther. 44(11), 572-579 (2006).
60. Böhmer GM, Nassr N, Wenger M et al. The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions. J. Clin. Pharmacol. 49(4), 389-397 (2009).
61. Böhmer GM, Gleiter CH, MG et al. No dose adjustment on coadministration of the PDE4 inhibitor roflumilast with a weak CYP3A, CYP1A2, and CYP2C19 inhibitor: An investigation using cimetidine. J. Clin. Pharmacol. DOI: 10.1177/0091270010368282 (2010) (Epub ahead of print).
62. Lahu G, Hünnemeyer A, von Richter O et al. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J. Clin. Pharmacol. 48(11), 1339-1349 (2008).
63. Lahu G, Hünnemeyer A, Herzog R et al. Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int. J. Clin. Pharmacol. Ther. 47(4), 236-245 (2009).
64. Lahu G, Nassr N, Herzog R et al. Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. J. Clin. Pharmacol. DOI: 10.1177/0091270010370590 (2010) (Epub ahead of print).
65. Nassr N, Lahu G, von Richter O et al. Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects. Br. J. Clin. Pharmacol. 63(3), 365-370 (2007).
66. Nassr N, Lahu G, Hünnemeyer A et al. Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast. J. Clin. Pharmacol. 47(5), 660-666 (2007).
67. Nassr N, Hünnemeyer A, Herzog R, von Richter O, Hermann R, Koch M. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br. J. Clin. Pharmacol. 68(4), 580-587 (2009).
68. von Richter O, Lahu G, Hünnemeyer A, Herzog R, Zech K, Hermann R. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin. Pharmacokinet. 46(7), 613-622 (2007).
69. Bredenbröker D, Syed J, Leichtl S, Rathgeb F, Wurst W. Roflumilast, a new orally active, selective phosphodiesterase 4 inhibitor, is effective in the treatment of chronic obstructive pulmonary disease. Eur. Respir. J. 20 (Suppl. 38), 374S (2002).
70. Böszörményi-Nagy G, Pieters WR, Steffen H et al. The effect of roflumilast treatment and subsequent withdrawal in patients with COPD. Proc. Am. Thorac. Soc. 2, A544 (2005).
71. Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: A randomised controlled trial. Lancet 366(948), 563-571 (2005). • A 6-month study of the efficacy of roflumilast in moderate-to-severe COPD.
72. Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care. Med. 176(2), 154-161 (2007). • A 1-year study reporting the benefits of roflumilast on lung function in severe, stable COPD.
73. Calverley PM, Fabbri LM, Rabe KF, Goehring UM, Martinez FJ. Efficacy of the PDE4 inhibitor roflumilast in COPD patients with chronic bronchitis. Eur. Respir. J. 34(Suppl. 53), 270S (2009).
74. Hanania NA, Brose M, Larsson T, Rabe KF. Efficacy of roflumilast in patients receiving concomitant treatments for chronic obstructive pulmonary disease over 12 months. Am. J. Respir. Crit Care Med. 181, A4435 (2010).
75. Paggiaro PL, Foden AP. Improvements in breathlessness in patients with chronic obstructive pulmonary disease treated with roflumilast and tiotropium. Chest 136, 3S-4S (2009).
76. Calverley P, Pauwels R, Vestbo J et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: A randomised controlled trial. Lancet 361(9356), 449-456 (2003).
77. Calverley P, Pauwels RA, Jones PW, Anderson JA, Vestbos J. The severity of airways obstruction as a determinant of treatment response in COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 1(3), 209-218 (2006).
78. Calverley PM, Anderson JA, Celli B et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 356(8), 775-789 (2007).
79. Joo MJ, Lee TA, Au DH, Fitzgibbon ML, Weiss KB. Medication use patterns associated with spirometry in diagnosing COPD. COPD 5(6), 360-368 (2008).
80. Wouters EFM, Teichmann P, Brose M, Rabe KF, Fabbri LM. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 181, A4473 (2010).
81. Burgel PR, Nesme-Meyer P, Chanez P et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 135(4), 975-982 (2009).
82. Calverley PMA, Martinez FJ, Goehring UM, Rennard SI. Defining patient populations in COPD: Experience with roflumilast. Presented at: 7th International Multidisciplinary Conference on Chronic Obstructive Pulmonary Disease (COPD7). Birmingham, UK, 30 June-2 July 2010 (Poster 48).
83. Rennard SI, Vestbo J. The many 'small COPDs': COPD should be an orphan disease. Chest 134(3), 623-627 (2008).
84. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: Molecular and cellular mechanisms. Eur. Respir. J. 22(4), 672-688 (2003).
85. Wood AM, Tan SL, Stockley RA. Chronic obstructive pulmonary disease: Towards pharmacogenetics. Genome Med. 1(11), 112 (2009).
86. Wouters EF, Teichmann P, Brose M, Göke B, Rabe KF, Fabbri LM. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on glucose homeostasis in patients with treatment-naïve diabetes. Am. J. Respir. Crit. Care Med. 181, A4471