No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: An open-label, randomised, actively controlled study

BMC Clinical Pharmacology

Volumn 11, Issue , 2011, Pages

  De Mey, Christian ^a   Nassr, Nassr ^b   Lahu, Gezim ^b  

^a ACPS Applied Clinical Pharmacology Services   (Germany)

^b Nycomed GmbH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

FORMOTEROL; FORMOTEROL FUMARATE; GLUCOSE; POTASSIUM; ROFLUMILAST; AMINOPYRIDINE DERIVATIVE; BENZAMIDE DERIVATIVE; BRONCHODILATING AGENT; CYCLOPROPANE DERIVATIVE; ETHANOLAMINE DERIVATIVE; PHOSPHODIESTERASE IV INHIBITOR;

ADULT; AREA UNDER THE CURVE; ARTICLE; BLOOD PRESSURE; BLOOD SAMPLING; CARDIOGRAPHY; CARDIOVASCULAR RISK; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; CONTROLLED STUDY; DRUG SAFETY; DRUG TOLERABILITY; ELECTROCARDIOGRAPHY; EOSINOPHIL COUNT; GLUCOSE BLOOD LEVEL; HUMAN; MALE; MAXIMUM PLASMA CONCENTRATION; NORMAL HUMAN; PHARMACODYNAMICS; QT INTERVAL; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; TACHYCARDIA; UNSPECIFIED SIDE EFFECT; URINALYSIS; BLOOD; CONTROLLED CLINICAL TRIAL; DRUG EFFECT; DRUG INTERACTION; HEART; HEART OUTPUT; HEART RATE;

ADULT; AMINOPYRIDINES; BENZAMIDES; BLOOD GLUCOSE; BRONCHODILATOR AGENTS; CARDIAC OUTPUT; CYCLOPROPANES; DRUG INTERACTIONS; ELECTROCARDIOGRAPHY; ETHANOLAMINES; HEART; HEART RATE; HUMANS; MALE; PHOSPHODIESTERASE 4 INHIBITORS; POTASSIUM;

EID: 79957654465     PISSN: None     EISSN: 14726904     Source Type: Journal    
DOI: 10.1186/1472-6904-11-7     Document Type: Article

References (55)

1. Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R, Schudt C, Tenor H. The preclinical pharmacology of roflumilast - a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2010, 23:235-256. 10.1016/j.pupt.2010.03.011, 20381629.
2. 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, 297:280-290.
3. Jones NA, Boswell-Smith V, Lever R, Page CP. The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther 2005, 18:93-101. 10.1016/j.pupt.2004.10.001, 15649851.
4. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001, 297:267-279.
5. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007, 62:1081-1087. 10.1136/thx.2006.075937, 2094292, 17573446.
6. 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 2005, 366:563-571. 10.1016/S0140-6736(05)67100-0, 16099292.
7. 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 2007, 176:154-161. 10.1164/rccm.200610-1563OC, 17463412.
8. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009, 374:685-694. 10.1016/S0140-6736(09)61255-1, 19716960.
9. Global Initiative for Chronic Obstructive Lung Disease Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Updated 2009) 2009, Bethesda: National Heart, Lung and Blood Institute, Global Initiative for Chronic Obstructive Lung Disease.
10. O'Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J, Marciniuk D, Balter M, Ford G, Gervais A, Lacasse Y, Maltais F, Road J, Rocker G, Sin D, Sinuff T, Voduc N. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2008 update - highlights for primary care. Can Respir J 2008, 15(Suppl A):1A-8A. 2802325, 18292855.
11. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004, 23:932-946. 10.1183/09031936.04.00014304, 15219010.
12. Calverley PM. COPD: what is the unmet need?. Br J Pharmacol 2008, 155:487-493. 2579674, 18794891.
13. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009, 374:695-703. 10.1016/S0140-6736(09)61252-6, 19716961.
14. Buenestado A, Naline EN, Chapelier AC, Bellamy JFB, Devillier PD. Roflumilast and its active metabolite inhibit LPS-induced cytokines production from human parenchymal and bronchial explants: interaction with formoterol [abstract]. Eur Respir J 2009, 34:581s.
15. Spina D. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs 2003, 63:2575-2594. 10.2165/00003495-200363230-00002, 14636078.
16. Spina D. PDE4 inhibitors: current status. Br J Pharmacol 2008, 155:308-315. 2567892, 18660825.
17. Anderson GP. Current issues with beta2-adrenoceptor agonists: pharmacology and molecular and cellular mechanisms. Clin Rev Allergy Immunol 2006, 31:119-130. 10.1385/CRIAI:31:2:119, 17085788.
18. Zaccolo M, Movsesian MA. cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res 2007, 100:1569-1578. 10.1161/CIRCRESAHA.106.144501, 17556670.
19. Cazzola M, Matera MG, Donner CF. Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs 2005, 65:1595-1610. 10.2165/00003495-200565120-00001, 16060696.
20. Hermann R, Lahu G, Huennemyer A, Knoerzer D, Bethke TD, Haverkamp W. No effect of roflumilast on cardiac repolarization in healthy subjects [abstract]. Eur Respir J 2006, 28(Suppl 50):660s.
21. 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 2004, 113:S220-S221.
22. Bethke TD, Böhmer GM, Hermann R, Hauns B, Fux R, Morike K, David M, Knoerzer D, Wurst W, Gleiter CH. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor. J Clin Pharmacol 2007, 47:26-36. 10.1177/0091270006294529, 17192499.
23. Hermann R, Nassr N, Lahu G, Peterfai E, Knoerzer D, Herzog R, Zech K, de Mey C. Steady-state pharmacokinetics of roflumilast and roflumilast N-oxide in patients with mild and moderate liver cirrhosis. Clin Pharmacokinet 2007, 46:403-416. 10.2165/00003088-200746050-00003, 17465639.
24. Hermann R, Siegmund W, Giessmann T, Westphal K, Weinbrenner A, Hauns B, Reutter F, Lahu G, Zech K, Bethke TD. The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide. J Clin Pharmacol 2007, 47:1005-1013. 10.1177/0091270007300950, 17660483.
25. Hermann R, Lahu G, Hauns B, Bethke T, Zech K. Total PDE4 inhibitory activity: a concept for evaluating pharmacokinetic alterations of roflumilast and roflumilast N-oxide in special populations and drug-drug interactions [abstract]. Eur Respir J 2006, 28:436s.
26. Lahu G, Hünnemeyer A, Herzog R, McCracken N, Hermann R, Elmlinger M, Zech K. Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int J Clin Pharmacol Ther 2009, 47:236-245.
27. Lahu G, Hünnemeyer A, von Richter O, Hermann R, Herzog R, McCracken N, Zech K. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J Clin Pharmacol 2008, 48:1339-1349. 10.1177/0091270008321941, 18757786.
28. 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 2007, 46:613-622. 10.2165/00003088-200746070-00006, 17596106.
29. Lahu G, Nassr N, Herzog R, Elmlinger M, Ruth P, Hinder M, Huennemeyer A. Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-Oxide. J Clin Pharmacol 2011, 51:586-593. 10.1177/0091270010370590, 20466871.
30. Bohmer GM, Gleiter CH, Morike K, Nassr N, Walz A, Lahu G. 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. 10.1177/0091270010368282, 20484614.
31. Nassr N, Huennemeyer A, Herzog R, von RO, Hermann R, Koch M, Duffy K, Zech K, Lahu G. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin Pharmacol 2009, 68:580-587. 10.1111/j.1365-2125.2009.03478.x, 2780283, 19843061.
32. Electronic Medicines Compendium Formoterol summary of product characteristics. 1950, Electronic Medicines Compendium., http://www.medicines.org.uk/EMC/medicine/19503/SPC/Formoterol+Easyhaler+12+micrograms+per+actuation+inhalation+powder/
33. Lecaillon JB, Kaiser G, Palmisano M, Morgan J, Della CG. Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer. Eur J Clin Pharmacol 1999, 55:131-138. 10.1007/s002280050607, 10335908.
34. de Mey C, Erb K, Schroeter V, Belz GG. Differentiation of inodilatory responses by non-invasive measures of cardiovascular performance in healthy man. Int J Clin Pharmacol Ther 1996, 34:525-532.
35. de Mey C, Erb KA. Usefulness, usability, and quality criteria for noninvasive methods in cardiovascular clinical pharmacology. J Clin Pharmacol 1997, 37:11S-20S. 10.1177/009127009703700117, 9048280.
36. Weissler AM, Harris WS, Schoenfeld CD. Systolic time intervals in heart failure in man. Circulation 1968, 37:149-159.
37. Kubicek WG, Karnegis JN, Patterson RP, Witsoe DA, Mattson RH. Development and evaluation of an impedance cardiac output system. Aerosp Med 1966, 37:1208-1212.
38. Geddes LA, Sadler C. The specific resistance of blood at body temperature. Med Biol Eng 1973, 11:336-339. 10.1007/BF02475543, 4746389.
39. Wezler K, Boeger A. Die dynamik des arteriellen. Systems. Ergebn Physiol 1939, 41:292-606.
40. Hodges JL, Lehmann EL. The efficiency of some nonparametric competitors of the t-test. Ann Math Statist 1956, 27:324-335.
41. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920, 7:353-370.
42. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med Scand 1920, 53:469-486.
43. de Mey C, Belz GG, Nixdorf U, Butzer R, Schroeter V, Meyer J, Erbel R. Relative sensitivity of four noninvasive methods in assessing systolic cardiovascular effects of isoproterenol in healthy volunteers. Clin Pharmacol Ther 1992, 52:609-619. 10.1038/clpt.1992.199, 1458770.
44. de Mey C, Enterling D, Hanft G. Noninvasive assessment of the inodilator action of amrinone in healthy man. Eur J Clin Pharmacol 1991, 40:373-378. 10.1007/BF00265846, 2050172.
45. de Mey C, Enterling D. Non-invasive estimates of cardiac performance during and immediately after single and repeated passive upright tilt in normal man: volume dependency of systolic time intervals and maximum velocity of transthoracic impedance changes. Am J Noninvasive Cardiol 1987, 1:188-196.
46. de Mey C, Hansen-Schmidt S, Enterling D. Food intake as a source of methodological bias in cardiovascular clinical pharmacology. Pharmaceut Med 1987, 2:251-257.
47. de Mey C, Hansen-Schmidt S, Enterling D. Postprandial haemodynamic changes: a source of bias in cardiovascular research affected by its own methodological bias. Cardiovasc Res 1988, 22:703-707. 10.1093/cvr/22.10.703, 3256414.
48. Kirby DA, Vatner SF. Enhanced responsiveness to carotid baroreceptor unloading in conscious dogs during development of perinephritic hypertension. Circ Res 1987, 61:678-686.
49. Carlsson E, Dahlof CG, Hedberg A, Persson H, Tangstrand B. Differentiation of cardiac chronotropic and inotropic effects of beta-adrenoceptor agonists. Naunyn Schmiedebergs Arch Pharmacol 1977, 300:101-105. 10.1007/BF00505039, 22823.
50. Bennett JA, Tattersfield AE. Time course and relative dose potency of systemic effects from salmeterol and salbutamol in healthy subjects. Thorax 1997, 52:458-464. 10.1136/thx.52.5.458, 1758570, 9176539.
51. Palmqvist M, Ibsen T, Mellen A, Lotvall J. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med 1999, 160:244-249.
52. Bateman ED, Rabe K, Calverley PMA, Goehring UM, Brose M, Bredenbrocker D, Fabbri LM. Roflumilast with long-acting β2 agonists for COPD: influence of exacerbation history. Eur Respir J 2011,
53. Lahu G, Hünnemeyer A, Diletti E, Elmlinger M, Ruth P, Zech K, McCracken N, Facius A. 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. 10.2165/11536600-000000000-00000, 20690782.
54. Jonsson G, Astrom A, Andersson P. Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver. Drug Metab Dispos 1995, 23:137-142.
55. Rennard SI, Calverley PM, Goehring UM, Bredenbroker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD. Respir Res 2011, 12:18. 10.1186/1465-9921-12-18, 3040135, 21272339.