Pharmacokinetic evaluation of roflumilast

Expert Opinion on Drug Metabolism and Toxicology

Volumn 7, Issue 12, 2011, Pages 1577-1591

  Lahu, Gezim ^a   Nassr, Nassr ^a   Hünnemeyer, Andreas ^a  

^a Nycomed GmbH   (Germany)

Author keywords

COPD; PDE4 inhibitors; Pharmacokinetics; Roflumilast

Indexed keywords

ALUMINUM MAGNESIUM HYDROXIDE; BUDESONIDE; CIMETIDINE; CYTOCHROME P450 INHIBITOR; DIGOXIN; ENOXACIN; ERYTHROMYCIN; FLUVOXAMINE; FORMOTEROL; KETOCONAZOLE; MIDAZOLAM; MONTELUKAST; PLACEBO; RIFAMPICIN; ROFLUMILAST; ROFLUMILAST N OXIDE; SALBUTAMOL; THEOPHYLLINE; UNCLASSIFIED DRUG; WARFARIN;

ABDOMINAL PAIN; AREA UNDER THE CURVE; ARTICLE; BODY WEIGHT; CHRONIC OBSTRUCTIVE LUNG DISEASE; DIARRHEA; DRUG ABSORPTION; DRUG ACTIVITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENTIATION; DRUG STRUCTURE; DRUG WITHDRAWAL; FOOD DRUG INTERACTION; GASTROINTESTINAL SYMPTOM; GENETIC POLYMORPHISM; GROUPS BY AGE; HEADACHE; HUMAN; KIDNEY DYSFUNCTION; LIVER DYSFUNCTION; MAXIMUM PLASMA CONCENTRATION; MENTAL DISEASE; NAUSEA; RACE DIFFERENCE; SEX DIFFERENCE; SIDE EFFECT; SMOKING; TIME TO MAXIMUM PLASMA CONCENTRATION; WEIGHT REDUCTION;

AMINOPYRIDINES; ANTI-INFLAMMATORY AGENTS; BENZAMIDES; CLINICAL TRIALS AS TOPIC; CYCLOPROPANES; CYTOCHROME P-450 CYP1A2; CYTOCHROME P-450 CYP3A; DRUG INTERACTIONS; HUMANS; PHOSPHODIESTERASE 4 INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 81855226433     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2011.632409     Document Type: Article

References (59)

1. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010;7:1128-38
2. Barnes PJ. Emerging pharmacotherapies for COPD. Chest 2008;134:1278-86
3. Celli BR. Update on the management of COPD. Chest 2008;133:1451-62
4. 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 Pharmacol Ther 2010;23:235-56
5. Calverley PM, 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;176:154-61
6. Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94
7. 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 2009;374:695-703
8. 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 2007;62:1081-7
9. Rabe KF, Bateman ED, O'Donnell D, et al. Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005;366:563-71
10. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 2001;108:671-80
11. Sanz MJ, Cortijo J, Morcillo EJ. PDE4 inhibitors as new anti-inflammatory drugs: Effects on cell trafficking and cell adhesion molecules expression. Pharmacol Ther 2005;106:269-97
12. Hermann R, Lahu G, Hauns B, et al. "Total PDE4 inhibitory activity": a concept for evaluating pharmacokinetic alterations of roflumilast and roflumilast N-oxide in special populations and drug-drug interactions. Eur Respir J 2006;28:436s
13. Tenor H, Hatzelmann A, Beume R, et al. Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics. Handb Exp Pharmacol 2011;204:85-119
14. Lahu G, Hunnemeyer A, Diletti E, et al. Population pharmacokinetic modelling of roflumilast and roflumilast N-oxide by total phosphodiesterase 4 inhibitory activity and development of a population pharmacodynamic-adverse Event model. Clin Pharmacokinet 2010;49:589-606
15. David M, Zech K, Seiberling M, et al. Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high oral bioavailability. J Allergy Clin Immunol 2004;113:S220-1
16. 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;47:26-36
17. Lahu G, Hunnemeyer 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;48:1339-49
18. Data on file, Summary of Clinical Pharmacology, Nycomed GmbH. 2009
19. 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;46:403-16
20. Hunnemeyer A, Hauns B, David M, et al. Pharmacokinetics and safety of roflumilast, a once daily, oral, selective PDE4 inhibitor, and its active metabolite roflumilast N-oxide in healthy subjects. J Allergy Clin Immunol 2004;113:S222
21. 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;46:1146-53
22. Data on file, Nycomed GmbH (previously Altana Pharma AG) 162/2003. 2010
23. Bebia Z, Buch SC, Wilson JW, et al. Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 2004;76:618-27
24. Parkinson A, Mudra DR, Johnson C, et al. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol 2004;199:193-209
25. Data on file, Nycomed GmbH (previously Altana Pharma AG) 318/ 2003. 2010
26. SPC. DAXAS 500 micrograms film-coated tablets. Available from: http://www.medicines.org.uk/emc/ medicine/23416/SPC/ [Last accessed 3 October 2011]
27. Bethke TD, Hartmann M, Hunnemeyer A, et al. Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study. Int J Clin Pharmacol Ther 2011;49:491-9
28. Data on file, Nycomed GmbH 19/2009. 2010
29. Eckermann G, Lagu G, Nassr N, Bethke TD. Absence of pharmacokinetic interaction between roflumilast and digoxin in healthy adults. J Clin Pharmacol 2010; E-pub ahead of print
30. Data on file, Nycomed GmbH (previously Altana Pharma AG) 21//2003. 2010
31. Data on file, Nycomed GmbH (previously Altana Pharma AG) 22/2003. 2010
32. Westlind-Johnsson A, Hermann R, Huennemeyer A, et al. Identification and characterization of CYP3A4. * 20, a novel rare CYP3A4 allele without functional activity. Clin Pharmacol Ther 2006;79:339-49
33. Lahu G, Hunnemeyer 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;47:236-45
34. 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;68:580-7
35. 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;63:365-70
36. von Richter O, Lahu G, Hunnemeyer A, et al. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin Pharmacokinet 2007;46:613-22
37. 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 2010;51:586-93
38. Jindal SK, Aggarwal AN, Chaudhry K, et al. A multicentric study on epidemiology of chronic obstructive pulmonary disease and its relationship with tobacco smoking and environmental tobacco smoke exposure. Indian J Chest Dis Allied Sci 2006;48:23-9
39. Funck-Brentano C, Raphael M, Lafontaine M, et al. Effects of type of smoking (pipe, cigars or cigarettes) on biological indices of tobacco exposure and toxicity. Lung Cancer 2006;54:11-18
40. Data on file, Nycomed GmbH (previously Byk Gulden Pharmaceuticals, Konstanz, Germany) 213/2000. 2000
41. Mokhlesi B, Morris AL, Huang CF, et al. Increased prevalence of gastroesophageal reflux symptoms in patients with COPD. Chest 2001;119:1043-8
42. Phulpoto MA, Qayyum S, Rizvi N, Khuhawar SM. Proportion of gastroesophageal reflux symptoms in patients with chronic obstructive pulmonary disease. J Pak Med Assoc 2005;55:276-9
43. 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;47:660-6
44. 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;44:572-9
45. De Mey C, Nassr N, Lahu G. No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study. BMC Clin Pharmacol 2011;11:7
46. 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;47:1005-13
47. Bohmer G, Gleiter CH, Hunnemeyer A, et al. Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults. Int J Clin Pharmacol Ther 2011;49:451-60
48. 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;49:389-97
49. McCracken N, Lahu G, Bethke TD. Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects. Int J Clin Pharmacol Ther 2011;49:388-96
50. Bohmer GM, Gleiter CH, Morike K, 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 2011;51:594-602
51. Rennard SI, Calverley PM, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast - The importance of defining different subsets of patients with COPD. Respir Res 2011;12:18
52. Calverley PMA, Fabbri LM, Rabe KF, Mosberg H. Roflumilast in the treatment of COPD: a pooled safety analysis [Poster 4732 2010]. Presented at the European Respiratory Society Annual Congress; 18 - 22 September 2010; Barcelona, Spain
53. White WB, Gorelick PB, Cooke G, et al. Major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: analysis of 14 pooled roflumilast studies. Am J Respir Crit Care Med 2011;183:A3092
54. Huennemeyer A, Nassr N, Bredenbroker D, Lahu G. Supra-therapeutic doses of roflumilast have no effect on cardiac repolarization in healthy subjects. Expert Opin Drug Saf 2011;10:509-19
55. Wouters EFM, Teichmann P, Brose M, et al. Effects of roflumilast, aphosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:A4473
56. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (updated 2010).National Heart, Lung and Blood Institute; Bethesda: 2010
57. Bateman ED, Rabe KF, Calverley PM, et al. Roflumilast with long-acting {beta} 2-agonists for COPD: influence of exacerbation history. Eur Respir J 2011;38:553-60
58. Wouters EF, Teichmann P, Brose M, et al. Effect of roflumilast on glucose levels in patients with COPD and diabetes mellitus type 2 [Poster 4002 2010]. Presented at the European Respiratory Society Annual Congress; 18 - 22 September 2010; Barcelona, Spain
59. Bohmer G, Gleiter CH, Hunnemeyer A, et al. Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults. Int J Clin Pharmacol Ther 2011;49:451-60