Roflumilast: First phosphodiesterase 4 inhibitor approved for treatment of COPD

Drug Design, Development and Therapy

Volumn 4, Issue , 2010, Pages 147-158

  Giembycz, Mark A ^a   Field, Stephen K ^a  

^a UNIVERSITY OF CALGARY   (Canada)

Author keywords

Chronic obstructive pulmonary disease; Exacerbation; Phosphodiesterase 4 inhibitor; Roflumilast

Indexed keywords

3 (3 CYCLOPENTYLOXY 4 METHOXYBENZYL) 6 ETHYLAMINO 8 ISOPROPYL 3H PURINE; ALPHA 2 MACROGLOBULIN; APTA 2217; B 9302 107; BAY 198004; BENZAMIDE; BUDESONIDE; BYK 20869; CILOMILAST; CIMETIDINE; CORTICOSTEROID; DIGOXIN; ENOXACIN; ERYTHROMYCIN; FLUTICASONE; FLUVOXAMINE; FORMOTEROL; INTERLEUKIN 8; KETOCONAZOLE; METHYLPREDNISOLONE; MONTELUKAST; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; PLACEBO; RIFAMPICIN; ROFLUMILAST; SALBUTAMOL; SALMETEROL; SILDENAFIL; THEOPHYLLINE; TIOTROPIUM BROMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; WARFARIN; AMINOPYRIDINE DERIVATIVE; BENZAMIDE DERIVATIVE; CYCLOPROPANE DERIVATIVE; PHOSPHODIESTERASE INHIBITOR;

ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; CHRONIC BRONCHITIS; CHRONIC OBSTRUCTIVE LUNG DISEASE; CONTROLLED RELEASE FORMULATION; DIARRHEA; DISEASE EXACERBATION; DISEASE SEVERITY; DRUG ANTAGONISM; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG CONTRAINDICATION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG POTENTIATION; DRUG RESPONSE; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; DRUG TOLERABILITY; DRUG WITHDRAWAL; EMPHYSEMA; GASTROINTESTINAL SYMPTOM; GASTROINTESTINAL TOXICITY; HUMAN; IC 50; IMMUNOMODULATION; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NONHUMAN; OUTCOME ASSESSMENT; PHARMACODYNAMICS; REVIEW; RHINOPHARYNGITIS; RISK REDUCTION; SIDE EFFECT; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION; UPPER RESPIRATORY TRACT INFECTION; WEIGHT REDUCTION; ADULT; ANIMAL; HOSPITALIZATION; LUNG FUNCTION TEST; PATHOPHYSIOLOGY; RANDOMIZED CONTROLLED TRIAL (TOPIC);

ADULT; AMINOPYRIDINES; ANIMALS; BENZAMIDES; CYCLOPROPANES; HUMANS; PHOSPHODIESTERASE 4 INHIBITORS; PHOSPHODIESTERASE INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RESPIRATORY FUNCTION TESTS; SEVERITY OF ILLNESS INDEX;

EID: 79851471591     PISSN: 11778881     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (83)

1. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am Respir Crit Care Med. 2007;176(6):532-555.
2. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance: United States, 1971-2000. MMWR CDC Surveill Summ. 2002;51(6):1-16.
3. Donaldson GC, Seemungal TA, Bhomik, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852.
4. Nie JX, Wang L, Upshur REG. Mortality of elderly patients in Ontario after hospital admission for chronic obstructive pulmonary disease. Can Respir J. 2009;14(8):485-489.
5. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. Am J Respir Crit Care Med. 1996;154(4 Pt1):959-967.
6. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. New Engl J Med. 2004;350(26):2645-2653.
7. Barnes PJ. The cytokine network in COPD. Am J Respir Cell Mol Biol. 2009;41(6):631-638.
8. Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: A systemic review and a meta-analysis. Thorax. 2004;59(7):574-580.
9. Barnes PJ, Celli B. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33(5):1165-1185.
10. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Immunol Rev. 2008;8(3):183-192.
11. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacol Rev. 2006;58(3):488-520.
12. Press NJ, Banner KH. PDE4 inhibitors - a review of the current field. Prog Med Chem. 2009;47(1):37-74.
13. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Antiinflammatory effects of low-dose oral theophylline in atopic asthma. Lancet. 1994;343(8904):1006-1008.
14. Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med. 1995;151(6):1907-1914.
15. Djukanovic R, Finnerty JP, Lee C, Wilson S, Madden J, Holgate ST. The effects of theophylline on mucosal inflammation in asthmatic airways: Biopsy results. Eur Respir J. 1995;8(5):831-833.
16. Finnerty JP, Lee C, Wilson S, Madden J, Djukanovic R, Holgate ST. Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: A placebo-controlled parallel group study. Eur Respir J. 1996;9(8):1672-1677.
17. Culpitt SV, de Matos C, Russell RE, Donnelly LE, Rogers DF, Barnes PJ. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;165(10):1371-1376.
18. Kobayashi M, Nasuhara Y, Betsuyaku T, et al. Effect of low-dose theophylline on airway inflammation in COPD. Respirology. 2004;9(2): 249-254.
19. Iiboshi H, Ashitani J, Katoh S, et al. Long-term treatment with theophylline reduces neutrophils, interleukin-8 and tumor necrosis factor-α in the sputum of patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2007;20(1):46-51.
20. Barnes PJ. Theophylline in chronic obstructive pulmonary disease. New horizons. Proc Am Thorac Soc. 2005;2(4):334-339.
21. Giembycz MA. Can the anti-inflammatory potential of PDE4 inhibitors be realized: Guarded optimism or wishful thinking? Br J Pharmacol. 2008;155(3):288-290.
22. Pages L, Gavalda A, Lehner MD. PDE4 inhibitors: A review of current developments (2005-2009). Expert Opin Ther Pat. 2009;19(11): 1501-1519.
23. Altana Roflumilast - APTA 2217, B9302-107, BY 217, BYK 20869. Drugs R D. 2004;5(3):176-181.
24. Sorbera LA, Leeson PA, Casterer J. Roflumilast. Drugs Future. 2000;25(12):1261-1264.
25. Card GL, England BP, Suzuki Y, et al. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004; 12(12):2233-2247.
26. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001;297(1):267-279.
27. Houslay MD, Schafer P, Zhang KY. Phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005;10(22):1503-1519.
28. Torphy TJ, Barnette MS, Underwood DC, et al. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: From concept to clinic. Pulm Pharmacol Ther. 1999;12(2):131-135.
29. Gale DD, Hofer P, Spina D, et al. Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. Pulm Pharmacol Ther. 2003;16(2):97-104.
30. Robichaud A, Stamatiou PB, Jin SL, et al. Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest. 2002;110(7):1045-1052.
31. Giembycz MA. 4D or not 4D - the emetogenic basis of PDE4 inhibitors uncovered? Trends Pharmacol Sci. 2002;23(12):548.
32. Giembycz MA. An update and appraisal of the cilomilast phase III clinical development programme for chronic obstructive pulmonary disease. Br J Clin Pharmacol. 2006;62(2):138-152.
33. Torphy TJ. Phosphodiesterase isozymes: Molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998;157(2):351-370.
34. Giembycz MA. Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma? Biochem Pharmacol. 1992;43(10):2041-2051.
35. Currie GP, Butler CA, Anderson WJ, Skinner C. Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: A new approach to oral treatment. Br J Clin Pharmacol. 2008;65(6):803-810.
36. Spina D. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs. 2003;63(23):2575-2594.
37. Hatzelmann A, Morcillo EJ, Lungarella G, et al. The preclinical pharmacology of roflumilast - A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmac Ther. 2010 Apr 7 [Epub ahead of print].
38. Field SK. Roflumilast: An oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma. Expert Opin Investig Drugs. 2008;17(5):811-818.
39. 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. 2001;297(1): 280-290.
40. Sanz MJ, Cortijo J, Taha MA, et al. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol. 2007;152(4):481-492.
41. Martorana PA, Lunghi B, Lucatelli M, De Cunto G, Beume R, Lungarella G. Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice. BMC Pulm Med. 2008;8:17.
42. Martorana PA, Beume R, Lucatelli M, Wollin L, Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med. 2005;172(7):848-853.
43. Fitzgerald MF, Spicer D, McAulay AE, et al. Roflumilast but not methylprednisolone inhibited cigarette-smoke-induced pulmonary inflammation in guinea pigs. Eur Respir J. 2006;28 Suppl 50:663S.
44. Togo S, Liu X, Wang X, et al. PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-β1-stimulated fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009;296(6):L959-L969.
45. Sabatini F, Petechia L, Boero S, et al. A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro. Pulm Pharmacol Ther. 2010 Mar 11. [Epub ahead of print].
46. Burgess JK, Oliver BG, Poniris MH, et al. A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro. J Allergy Clin Immunol. 2006;118(3):649-657.
47. Wollin L, Bundshuh DS, Wohlsen A, Marx D, Beume R. Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors. Pulm Pharmacol Ther. 2006; 19(5):343-352.
48. Wollin L, Marx D, Wohlsen A, Beume R. Roflumilast inhibition of pulmonary leukotriene production and bronchoconstriction in ovalbumin-sensitized and -challenged guinea pigs. J Asthma. 2005; 42(10):873-878.
49. Grootendorst DC, Gauw SA, Baan R, et al. Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease? Pulm Pharmacol Ther. 2003;16(2):115-120.
50. Grootendorst DC, Gauw SA, Verhoosel RM, et al. The PDE4 inhibitor roflumilast reduces sputum neutrophil and eosinophil numbers in patients with COPD. Thorax. 2007;62(12):1081-1087.
51. Hohlfeld JM, Schoenfeld K, Lavae-Mokhtari M, et al. Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: A randomized placebo-controlled trial. Pulm Pharmacol Ther. 2008;21(4):616-623.
52. Timmer W, Leclerc V, Birraux J, et al. The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo. J Clin Pharmacol. 2002;42(3):297-303.
53. Gamble E, Grootendorst DC, Brightling CE, et al. Anti-inflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003; 168(8):976-982.
54. Grootendorst DC, Gauw SA, Benschop PN, Sterk PJ, Hiemstra PS, Rabe KF. Efficacy of the novel phosphodiesterase-4 inhibitor BAY 19-8004 on lung function and airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). Pulm Pharmacol Ther. 2003;16(6):341-347.
55. Bethke TD, Bohmer 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. 2007;47(1):26-36.
56. Hauns B, Hermaan 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. 2006;46(10):1146-1153.
57. Neville KA, Szefler SJ, Abdel-Rahman SM, et al. Single-dose pharmacokinetics of roflumilast in children and adolescents. J Clin Pharmacol. 2008;48(8):978-985.
58. Nassr N, Huennemeyer A, Herzog R, et al. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin Pharmacol. 2009;68(4):580-587.
59. David M, Zech K, Seiberling M, Weimar C, Bethke TD. Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability. J Allergy Clin Immunol. 2004;113(1):S220-S221.
60. Nassr N, Lahu G, Hunnemeyer A, et al. Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast. J Clin Pharmacol. 2007;47(5):660-666.
61. Lahu G, Huennemeyer 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. 2008;48(11):1339-1339.
62. Rabe KF, Bateman ED, O'Donnell DE, et al. Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: A randomized controlled trial. Lancet. 2005;366(9485):563-571.
63. Calverley PMA, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(2):154-161.
64. Rennard SI, Calverley PMA, Rempel A, et al. The effect of roflumilast treatment on exacerbations in patients with COPD - results of a pooled analysis of two 1-year studies. Am J Respir Crit Care Med. 2008;177:A963.
65. Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomized clinical trials. Lancet. 2009;374(9691):684-695.
66. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. New Engl J Med. 2007;356(8):775-789.
67. Tashkin DP, Celli B, Senn S, et al. A four-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15): 1543-1554.
68. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: Two randomized clinical trials. Lancet. 2009;374(9691):695-703.
69. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med. 2007;146(8):545-555.
70. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;153(3):967-975.
71. O'Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(5):770-777.
72. Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med. 2007;176(2):162-166.
73. Corren J, Casale TB, Lanier B, Buhl R, Holgate S, Jimenez P. Safety and tolerability of omalizumab. Clin Exp Allergy. 39(6):788-797.
74. Hermann R, Nassr N, Lahu G, et al. Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis. Clin Pharmacokinet. 2007;46(5):403-416.
75. 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. 2006;46(10):1146-1153.
76. 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. 2007;63(3):365-370.
77. Bohmer 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. 2009;49(4):389-397.
78. Lahu G, Huennemeyer 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. 2009;47(4):236-245.
79. Hermann R, Siegmund W, Giessmann T, et al. The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide. J Clin Pharmacol. 2007; 47(8):1005-1013.
80. 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. 2006;44(11):572-579.
81. Jusko WJ. Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev. 1979;9(2):221-236.
82. Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther. 1976;19(5 Pt 1):546-551.
83. Powell JR, Vozeh S, Hopewell P, Costello J, Sheiner LB, Riegelman S. Theophylline disposition in acutely ill hospitalized patients. The effect of smoking, heart failure, severe airway obstruction, and pneumonia. Am Rev Respir Dis. 1978;118(2):229-238.