Co-administration of rivaroxaban with drugs that share its elimination pathways: Pharmacokinetic effects in healthy subjects

British Journal of Clinical Pharmacology

Volumn 76, Issue 3, 2013, Pages 455-466

  Mueck, Wolfgang ^a   Kubitza, Dagmar ^a   Becka, Michael ^a  

^a BAYER PHARMA AG   (Germany)

Author keywords

Cytochrome P450; Drug interactions; Healthy subjects; P glycoprotein; Rivaroxaban

Indexed keywords

BREAST CANCER RESISTANCE PROTEIN; CLARITHROMYCIN; CYTOCHROME P450 3A4; ERYTHROMYCIN; FLUCONAZOLE; KETOCONAZOLE; MIDAZOLAM; MULTIDRUG RESISTANCE PROTEIN; RITONAVIR; RIVAROXABAN;

AREA UNDER THE CURVE; ARTICLE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG ELIMINATION; DRUG EXPOSURE; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; ELECTROCARDIOGRAM; FATIGUE; HUMAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); SIDE EFFECT; UNSPECIFIED SIDE EFFECT; VITAL SIGN;

CYTOCHROME P450; DRUG INTERACTIONS; HEALTHY SUBJECTS; P-GLYCOPROTEIN; RIVAROXABAN;

ADOLESCENT; ADULT; ANTICOAGULANTS; CLARITHROMYCIN; CYTOCHROME P-450 CYP3A; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; ENZYME INHIBITORS; ERYTHROMYCIN; HUMANS; KETOCONAZOLE; METABOLIC CLEARANCE RATE; MIDAZOLAM; MIDDLE AGED; MORPHOLINES; P-GLYCOPROTEIN; SUBSTRATE SPECIFICITY; THIOPHENES; YOUNG ADULT;

EID: 84877289110     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.12075     Document Type: Article

References (41)

1. Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, Straub A. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 - an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-521.
2. Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct Factor Xa inhibitor rivaroxaban. J Thromb Haemost 2007; 5: 886-888.
3. Biemond BJ, Perzborn E, Friederich PW, Levi M, Buetehorn U, Büller HR. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 59-7939) - an oral, direct Factor Xa inhibitor. Thromb Haemost 2007; 97: 471-477.
4. Perzborn E, Arndt B, Harwardt M, Lange U, Fischer E, Trabant A. Antithrombotic efficacy of BAY 59-7939 - an oral, direct Factor Xa inhibitor - compared with fondaparinux in animal arterial thrombosis and thromboembolic death models. Eur Heart J 2005; 26 (Suppl.): Abstract P2943.
5. Turpie AGG, Lassen MR, Eriksson BI, Gent M, Berkowitz SD, Misselwitz F, Bandel TJ, Homering M, Westermeier T, Kakkar AK. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105: 444-453.
6. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
7. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
8. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KAA, Califf RM, ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
9. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
10. Xarelto® (rivaroxaban). Bayer Pharma AG Summary of Product Characteristics. 2012. Available at http://www.xarelto.com/html/downloads/Xarelto-Prescribing_Information-Nov-2012.pdf (last accessed 11 December 2012).
11. Xarelto® (rivaroxaban). Janssen Pharmaceuticals Inc Prescribing Information. 2012. Available at http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf (last accessed 11 December 2012).
12. Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos 2009; 37: 1056-1064.
13. Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, Lufft V, Wand DD, Philipp T, Bruck H. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010; 70: 703-712.
14. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
15. Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 2011; 338: 372-380.
16. Cardiovascular and Renal Drugs Advisory Committee. FDA Advisory Committee Briefing Document. 2009. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM181524.pdf (last accessed 13 December 2012).
17. European Medicines Agency. CHMP assessment report for Xarelto EMEA/543519/2008. 2008. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000944/WC500057122.pdf (last accessed 13 December 2012).
18. Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxaban - an oral, direct Factor Xa inhibitor - in liver microsomes and hepatocytes of rat, dog and man. Drug Metab Dispos 2009; 37: 1046-1055.
19. Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor - in healthy subjects. Int J Clin Pharmacol Ther 2007; 45: 335-344.
20. Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, Gent M, Haas S, Huisman MV, Kakkar AK, Kälebo P, Kwong LM, Misselwitz F, Turpie AGG. Population pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct Factor Xa inhibitor - in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: 203-216.
21. von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Duan SX, Fogelman SM, Daily JP, Harmatz JS, Shader RI. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol 1998; 38: 106-111.
22. Wang JS, Wen X, Backman JT, Taavitsainen P, Neuvonen PJ, Kivisto KT. Midazolam alpha-hydroxylation by human liver microsomes in vitro: inhibition by calcium channel blockers, itraconazole and ketoconazole. Pharmacol Toxicol 1999; 85: 157-161.
23. Committee for Proprietary Medicinal Products (CPMP). Note for guidance on the investigation of drug interactions CPMP/EWP/560/95. 1997. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002966.pdf (last accessed 13 December 2012).
24. Food and Drug Administration. Guidance for Industry. Drug interaction studies - study design, data analysis, implications for dosing, and labeling recommendations. Draft Guidance 2012. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf (last accessed 13 December 2012).
25. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. No interaction between the novel, oral direct Factor Xa inhibitor BAY 59-7939 and digoxin. J Clin Pharmacol 2006; 46: Abstract 11.
26. Holtzman CW, Wiggins BS, Spinler SA. Role of P-glycoprotein in statin drug interactions. Pharmacotherapy 2006; 26: 1601-1607.
27. Kubitza D, Mueck W, Becka M. No interaction between rivaroxaban - a novel, oral, direct Factor Xa inhibitor - and atorvastatin. Pathophysiol Haemost Thromb 2008; 36: Abstract P062.
28. Kronbach T, Mathys D, Umeno M, Gonzalez FJ, Meyer UA. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 1989; 36: 89-96.
29. Mao Q, Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J 2005; 7: E118-E133.
30. Gupta A, Unadkat JD, Mao Q. Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP). J Pharm Sci 2007; 96: 3226-3235.
31. Gupta A, Zhang Y, Unadkat JD, Mao Q. HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther 2004; 310: 334-341.
32. Wakasugi H, Yano I, Ito T, Hashida T, Futami T, Nohara R, Sasayama S, Inui K. Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther 1998; 64: 123-128.
33. Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16: 408-414.
34. Zhao P, Ragueneau-Majlessi I, Zhang L, Strong JM, Reynolds KS, Levy RH, Thummel KE, Huang SM. Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole: a simulation study. J Clin Pharmacol 2009; 49: 351-359.
35. Rohde G. Determination of rivaroxaban - a novel, oral, direct Factor Xa inhibitor - in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 872: 43-50.
36. Gheorghiade M, Van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation 2006; 113: 2556-2564.
37. Kumar A, Cannon CP. Importance of intensive lipid lowering in acute coronary syndrome and percutaneous coronary intervention. J Interv Cardiol 2007; 20: 447-457.
38. Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A, Schneck DW. The effect of erythromycin on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol 2003; 59: 51-56.
39. Luurila H, Olkkola KT, Neuvonen PJ. Interaction between erythromycin and nitrazepam in healthy volunteers. Pharmacol Toxicol 1995; 76: 255-258.
40. Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50: 675-686.
41. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 - an oral, direct Factor Xa inhibitor - after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-880.