Darexaban (YM150), an oral direct factor Xa inhibitor, has no effect on the pharmacokinetics of digoxin

  • Takeshi KadokuraEmail author
  • Dorien Groenendaal
  • Marten Heeringa
  • Roelof Mol
  • Frank Verheggen
  • Alberto Garcia-Hernandez
  • Hartmut Onkels
Original Paper


To investigate the impact of the direct Factor Xa inhibitor darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double-blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6–7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin C max,ss and AUC0–24h,ss with and without darexaban-MR co-administration were within 0.80–1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for C max,ss and AUC0–24h,ss of digoxin plus darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94–1.12) and 1.11 (90 % CI: 1.05–1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80–1.25, indicating a lack of drug–drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co-administration of darexaban-MR did not impact the steady-state PK profile of digoxin.


Darexaban Factor Xa inhibitor Anticoagulant Pharmacokinetics Digoxin P-glycoprotein 



This study was funded by Astellas. Editorial support was provided by Medicus International and funded by Astellas. Takeshi Kadokura is an employee of Astellas Pharma Inc. Dorien Groenendaal, Alberto Garcia-Hernandez, Marten Heeringa, Roelof Mol, Frank Verheggen, and Hartmut Onkels are all employees of Astellas Pharma Global Development Europe.


  1. Groenendaal-van de Meent D et al (2010) YM150, an oral direct inhibitor of factor Xa, demonstrated a predictable and dose-proportional pharmacokinetic/pharmacodynamic profile after single and multiple dosing: results from three studies. Blood 116: Abstract No. 3323Google Scholar
  2. Eriksson BI et al (2011) ONYX-3, a double-blind comparison of once- or twice-daily dosing with darexaban (YM150) (30 or 60 mg daily) for preventing venous thromboembolism after elective hip arthroplasty. J Thromb Haemost 9(Suppl 2):855Google Scholar
  3. Hashimoto T et al (2011) Drug transporters involved in the pharmacokinetics of YM150, a novel factor Xa inhibitor in humans. Drug Metab Rev 43(S1):80Google Scholar
  4. Ansell J et al (2004) The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):204S–233SPubMedCrossRefGoogle Scholar
  5. Balayssac D et al (2005) Does inhibition of P-glycoprotein lead to drug–drug interactions? Toxicol Lett 156(3):319–329PubMedCrossRefGoogle Scholar
  6. Barclay M, Begg E (2003) The practice of digoxin therapeutic drug monitoring. N Z Med J 116:U704PubMedGoogle Scholar
  7. Bauman JL et al (2006) A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med 166(22):2539–2545PubMedCrossRefGoogle Scholar
  8. Bradley BC et al (2000) Frequency of anticoagulation for atrial fibrillation and reasons for its non-use at a Veterans Affairs medical center. Am J Cardiol 85(5):568–572PubMedCrossRefGoogle Scholar
  9. Bungard TJ et al (2000) Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 160(1):41–46PubMedCrossRefGoogle Scholar
  10. COUMADIN (warfarin sodium) tablets [prescribing information] (2011) US Food and Drug Administration, 2011. Accessed 6 Jun 2013
  11. LANOXIN (digoxin) tablets [prescribing information] (2012) US food and drug administration, 2012. Accessed 27 Mar 2013
  12. Eriksson BI et al (2007) A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery. J Thromb Haemost 5(8):1660–1665PubMedCrossRefGoogle Scholar
  13. Eriksson BI et al (2010) Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2). J Thromb Haemost 8(4):714–721PubMedCrossRefGoogle Scholar
  14. European Heart Rhythm Association (2010) Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 31(19):2369–2429CrossRefGoogle Scholar
  15. Food and Drug Administration (2012) Drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. DRAFT GUIDANCE February 2012. Available at: Accessed 19 Oct 2012
  16. Friberg L et al (2006) Stroke prophylaxis in atrial fibrillation: who gets it and who does not? Report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study). Eur Heart J 27(16):1954–1964PubMedCrossRefGoogle Scholar
  17. Fromm MF et al (1999) Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 99(4):552–557PubMedCrossRefGoogle Scholar
  18. Frykman V et al (2001) Management of atrial fibrillation: discrepancy between guideline recommendations and actual practice exposes patients to risk for complications. Eur Heart J 22(20):1954–1959PubMedCrossRefGoogle Scholar
  19. Fuji T, Nakamura M, Takeuchi M, Darexaban for the prevention of venous thromboembolism in Asian patients undergoing orthopedic surgery: results from two randomized, placebo-controlled, double-blind studies. Clin Appl Thromb Hemost (in press)Google Scholar
  20. Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146(12):857–867PubMedCrossRefGoogle Scholar
  21. Hashimoto T et al (2013) Absorption, metabolism and disposition of darexaban (YM150), a new direct factor Xa inhibitor in humans. Xenobiotica 43(6):534–547Google Scholar
  22. Huffman DH, Manion CV, Azarnoff DL (1975) Intersubject variation in absorption of digoxin in normal volunteers. J Pharm Sci 64(3):433–437PubMedCrossRefGoogle Scholar
  23. Iwatsuki Y et al (2011) Biochemical and pharmacological profiles of darexaban, an oral direct factor Xa inhibitor Eur. J. Pharmacol 673:49–55Google Scholar
  24. Johne A et al (1999) Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 66(4):338–345PubMedCrossRefGoogle Scholar
  25. Kovarik JM et al (1999) Longitudinal assessment of a P-glycoprotein-mediated drug interaction of valspodar on digoxin. Clin Pharmacol Ther 66(4):391–400PubMedCrossRefGoogle Scholar
  26. Lip GY, Lim HS (2007) Atrial fibrillation and stroke prevention. Lancet Neurol 6(11):981–993PubMedCrossRefGoogle Scholar
  27. Mant J et al (2007) Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 370(9586):493–503PubMedCrossRefGoogle Scholar
  28. Mendell J, Noveck RJ, Shi M (2012) Pharmacokinetics of the direct factor Xa inhibitor edoxaban and digoxin administered alone and in combination. J Cardiovasc Pharmacol 60(4):335–341PubMedCrossRefGoogle Scholar
  29. Mittal MK, Chockalingam P, Chockalingam A (2011) Contemporary indications and therapeutic implications for digoxin use. Am J Ther 18(4):280–287PubMedCrossRefGoogle Scholar
  30. Miyasaka Y et al (2006) Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 114(2):119–125PubMedCrossRefGoogle Scholar
  31. Piccini JP et al (2009) Quality of care for atrial fibrillation among patients hospitalized for heart failure. J Am Coll Cardiol 54(14):1280–1289PubMedCrossRefGoogle Scholar
  32. Rathore SS et al (2003) Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 289(7):871–878PubMedCrossRefGoogle Scholar
  33. Reynolds MW et al (2004) Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 126(6):1938–1945PubMedCrossRefGoogle Scholar
  34. Rodgers GM et al (2011) Efficacy of the oral FXa inhibitor, darexaban (YM150) on biomarkers for thrombogenesis in 1,297 patients with non-valvular atrial fibrillation: phase IIb dose confirmation study (OPAL-2). J Thromb Haemost 9(Suppl 2):887Google Scholar
  35. Schnabel RB et al (2010) Validation of an atrial fibrillation risk algorithm in whites and African Americans. Arch Intern Med 170(21):1909–1917PubMedCentralPubMedCrossRefGoogle Scholar
  36. Steg PG et al (2011) RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 32(20):2541–2554PubMedCentralPubMedCrossRefGoogle Scholar
  37. The European Medicines Agency (2012) Guideline on the investigation of drug interactions. Available at: Accessed 1 Apr 2013
  38. Weber C et al (1999) The effect of Bosentan on the pharmacokinetics of digoxin in healthy male subjects. Br J Clin Pharmacol 47(6):701–706PubMedCentralPubMedCrossRefGoogle Scholar
  39. Westphal K et al (2000) Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein. Clin Pharmacol Ther 68(1):6–12PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag France 2013

Authors and Affiliations

  • Takeshi Kadokura
    • 1
    Email author
  • Dorien Groenendaal
    • 2
  • Marten Heeringa
    • 2
  • Roelof Mol
    • 2
  • Frank Verheggen
    • 2
  • Alberto Garcia-Hernandez
    • 2
  • Hartmut Onkels
    • 2
  1. 1.Astellas Pharma IncItabashi-kuJapan
  2. 2.Astellas Pharma Global Development EuropeLeidenThe Netherlands

Personalised recommendations