Absence of pharmacokinetic interaction between roflumilast and digoxin in healthy adults

Journal of Clinical Pharmacology

Volumn 52, Issue 2, 2012, Pages 251-257

  Eckermann, Gabriel ^b   Lahu, Gezim ^a   Nassr, Nassr ^a   Bethke, Thomas D ^a  

^a Nycomed Deutschland GmbH   (Germany)

^b District Hospital Kaufbeuren   (Germany)

Author keywords

digoxin; interaction; P glycoprotein; pharmacokinetics; Roflumilast

Indexed keywords

DIGOXIN; ROFLUMILAST; AMINOPYRIDINE DERIVATIVE; ANTIARRHYTHMIC AGENT; BENZAMIDE DERIVATIVE; CYCLOPROPANE DERIVATIVE; PHOSPHODIESTERASE IV INHIBITOR;

ABDOMINAL PAIN; ADULT; ARTICLE; CONTROLLED STUDY; CROSSOVER PROCEDURE; DIARRHEA; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG SAFETY; DRUG TOLERABILITY; FEMALE; HEADACHE; HUMAN; HUMAN EXPERIMENT; MALE; NORMAL HUMAN; RANDOMIZED CONTROLLED TRIAL; SINGLE DRUG DOSE; STEADY STATE; BLOOD; DRUG INTERACTION; YOUNG ADULT;

ADULT; AMINOPYRIDINES; ANTI-ARRHYTHMIA AGENTS; BENZAMIDES; CROSS-OVER STUDIES; CYCLOPROPANES; DIGOXIN; DRUG INTERACTIONS; FEMALE; HEALTHY VOLUNTEERS; HUMANS; MALE; PHOSPHODIESTERASE 4 INHIBITORS; YOUNG ADULT;

EID: 84856610748     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1177/0091270010389467     Document Type: Article

References (24)

1. 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
2. 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
3. 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 (Pubitemid 32242588)
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 (Pubitemid 32242587)
5. Hatzelmann A, Morcillo EC, 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.:
6. 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. 2007 ; 47: 26-36 (Pubitemid 44973995)
7. Tanigawara Y, Okamura N, Hirai M, et al. Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther. 1992 ; 263: 840-845
8. Food and Drug Administration. Guidance for Industry Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling. Draft Guidance. Rockville, MD: US Department of Health and Human Services, FDA; 2006. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf.
9. 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: 339-349
10. Dehghani P, Ignaszewski A. Digoxin toxicity: regaining a level of control. Perspect Cardiol. 2004 ; 8: 12-16
11. Pickett JR, Dickinson ET. Dealing with DIG. A comprehensive review of digoxin and its therapeutic and toxic effects. JEMS. 2005 ; 30: 70-84
12. Ma JD, Tsunoda SM, Bertino JS, Trivedi M, Beale KK, Nafziger AN. Evaluation of in vivo p-glycoprotein phenotyping probes: a need for validation. Clin Pharmacokinet. 2010 ; 49: 223-237
13. Reuning RH, Sams RA, Notari RE. Role of pharmacokinetics in drug dosage adjustment. I. Pharmacologic effect kinetics and apparent volume of distribution of digoxin. J Clin Pharmacol New Drugs. 1973 ; 13: 127-141
14. Slatton ML, Irani WN, Hall SA, et al. Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm?. J Am Coll Cardiol. 1997 ; 29: 1206-1213 (Pubitemid 27201936)
15. Beasley R, Smith DA, McHaffie DJ. Exercise heart rates at different serum digoxin concentrations in patients with atrial fibrillation. Br Med J (Clin Res Ed). 1985 ; 290: 9-11 (Pubitemid 15075972)
16. Zussman BD, Kelly J, Murdoch RD, Clark DJ, Schubert C, Collie H. Cilomilast: pharmacokinetic and pharmacodynamic interactions with digoxin. Clin Ther. 2001 ; 23: 921-931 (Pubitemid 32554573)
17. Giembycz MA. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2001 ; 10: 1361-1379 (Pubitemid 32633576)
18. Field SK. Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma. Expert Opin Investig Drugs. 2008 ; 17: 811-818 (Pubitemid 351843624)
19. 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: 236-245
20. 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: 1339-1349
21. von Richter O, Lahu G, Huennemeyer 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 (Pubitemid 47025361)
22. 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.:
23. Böhmer GM, Gleiter CH, Mörike 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.:
24. 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: 580-587