Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment

Clinical Pharmacokinetics

Volumn 52, Issue 4, 2013, Pages 243-254

  Graff, Jochen ^a   Harder, Sebastian ^a  

^a GOETHE UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; APIXABAN; ASPARTATE AMINOTRANSFERASE; DABIGATRAN ETEXILATE; EDOXABAN; RIVAROXABAN;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANTICOAGULANT THERAPY; AREA UNDER THE CURVE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BLEEDING; BLOOD CLOTTING DISORDER; CHILD PUGH SCORE; CLINICAL TRIAL (TOPIC); DISEASE SEVERITY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG MECHANISM; DRUG METABOLISM; DRUG URINE LEVEL; HUMAN; LIVER CIRRHOSIS; LIVER DYSFUNCTION; LUNG EMBOLISM; MAXIMUM PLASMA CONCENTRATION; PARTIAL THROMBOPLASTIN TIME; PATHOPHYSIOLOGY; PHARMACODYNAMICS; PLASMA CONCENTRATION-TIME CURVE; PRIORITY JOURNAL; PROTHROMBIN TIME; REVIEW; RISK FACTOR; SINGLE DRUG DOSE; SURVIVAL RATE; THROMBOSIS PREVENTION; TREATMENT CONTRAINDICATION; VENOUS THROMBOEMBOLISM;

ABSORPTION; ANTICOAGULANTS; BENZIMIDAZOLES; DOSE-RESPONSE RELATIONSHIP, DRUG; FACTOR XA; HUMANS; LIVER DISEASES; METABOLIC CLEARANCE RATE; MORPHOLINES; PYRAZOLES; PYRIDINES; PYRIDONES; THIAZOLES; THIOPHENES; THROMBIN; TISSUE DISTRIBUTION; VENOUS THROMBOEMBOLISM;

EID: 84877069414     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-013-0034-0     Document Type: Review

References (85)

1. Deitelzweig SB, Lin J, Lin G. Preventing venous thromboembolism following orthopedic surgery in the United States: impact of special populations on clinical outcomes. Clin Appl Thromb Hemost. 2011;17(6):640-50.
2. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe: the number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756-64.
3. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl):234S-56S.
4. Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol. 2010;30(3):376-81.
5. Jimenez D, Yusen RD, Ramacciotti E. Apixaban: an oral direct factor-xa inhibitor. Adv Ther. 2012;29(3):187-201.
6. Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010;30(10):1885-9.
7. Ahrens I, Peter K, Lip GY, Bode C. Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Discov Med. 2012;13(73):445-50.
8. Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor xa inhibitor. Drugs. 2011;71(12):1503-26.
9. Harder S. Renal profiles of anticoagulants. J Clin Pharmacol. 2012;52(7):964-75.
10. Thachil J. Relevance of clotting tests in liver disease. Postgrad Med J. 2008;84(990):177-81.
11. Baczek VL, Chen WT, Kluger J, Coleman CI. Predictors of warfarin use in atrial fibrillation in the United States: a systematic review and meta-analysis. BMC Fam Pract. 2012;13:5.
12. Deitelzweig SB, Lin J, Kreilick C, Hussein M, Battleman D. Warfarin therapy in patients with venous thromboembolism: patterns of use and predictors of clinical outcomes. Adv Ther. 2010;27(9):623-33.
13. Le Couteur DG, Fraser R, Hilmer S, Rivory LP, McLean AJ. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet. 2005;44(2):187-200.
14. Herrlinger C, Klotz U. Drug metabolism and drug interactions in the elderly. Best Pract Res Clin Gastroenterol. 2001;15(6):897-918.
15. Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet. 1995;29(5):370-91.
16. Delco F, Tchambaz L, Schlienger R, Drewe J, Krahenbuhl S. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529-45.
17. Blaschke TF, Rubin PC. Hepatic first-pass metabolism in liver disease. Clin Pharmacokinet. 1979;4(6):423-32.
18. 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(5):1056-64.
19. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74-81.
20. Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36(2):386-99.
21. Stangier J, Stahle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48(12):1411-9.
22. Weinz C, Buetehorn U, Daehler HP, et al. Pharmacokinetics of BAY 59-7939-an oral, direct Factor Xa inhibitor-in rats and dogs. Xenobiotica. 2005;35(9):891-910.
23. He K, Luettgen JM, Zhang D, et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet. 2011;36(3):129-39.
24. Reichen J. The role of the sinusoidal endothelium in liver function. News Physiol Sci. 1999;14:117-21.
25. Frye RF, Zgheib NK, Matzke GR, et al. Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther. 2006;80(3):235-45.
26. Chalasani N, Gorski JC, Patel NH, Hall SD, Galinsky RE. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology. 2001;34(6):1103-8.
27. Elbekai RH, Korashy HM, El-Kadi AO. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr Drug Metab. 2004;5(2):157-67.
28. Orlando R, Mussap M, Plebani M, et al. Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chem. 2002;48(6 Pt 1):850-8.
29. Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Coagulation disorders in liver disease. Semin Liver Dis. 2002;22(1):83-96.
30. Caldwell SH, Hoffman M, Lisman T, et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006;44(4):1039-46.
31. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147-56.
32. Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41(3):553-8.
33. Roberts LN, Patel RK, Arya R. Haemostasis and thrombosis in liver disease. Br J Haematol. 2010;148(4):507-21.
34. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646-9.
35. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124(1):91-6.
36. Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D, Burroughs AK. Systematic review: the model for end-stage liver disease-should it replace Child-Pugh's classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 2005;22(11-12):1079-89.
37. FDA. Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labelling. 2003. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf. Accessed 15 Jan 2013.
38. EMEA. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. 2005. http://www.ema. europa.eu/docs/en-GB/document-library/Scientific-guideline/2009/09/WC500003122. pdf. Accessed 15 Jan 2013.
39. Spray JW, Willett K, Chase D, Sindelar R, Connelly S. Dosage adjustment for hepatic dysfunction based on Child-Pugh scores. Am J Health Syst Pharm 2007; 64(7):692-3.
40. Perzborn E, Strassburger J, Wilmen A, et al. 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(3):514-21.
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(12):873-80.
42. 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(4):886-8.
43. 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(4):412-21.
44. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet. 2009;48(1):1-22.
45. 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(1):372-80.
46. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban: an oral, direct Factor Xa inhibitor [abstract]. Blood 2006;108: abstract 905.
47. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47(2):218-26.
48. Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703-12.
49. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011;105(3):444-53.
50. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2012;363(26):2499-510.
51. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
52. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91.
53. Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban: an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. Epub 2013 Jan 8. doi: 10.1111/bcp.12054.
54. Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008;6(5):820-9.
55. Frost C, Yu Z, Nepal S, Mosqueda-Garcia R, Shenker A. Apixaban, an oral direct Factor Xa inhibitor: single-dose safety, pharmacokinetics and pharmacodynamics in healthy volunteers [abstract]. J Thromb Haemost 2007;5 (Suppl 1): abstract P-M-665.
56. Frost C, Yu Z, Moore K, et al. Apixaban, an oral direct factor Xa inhibitor: multiple-dose safety, pharmacokinetics, and pharmacodynamics in healthy subjects [abstract]. J Thromb Haemost 2007;5 (Suppl 2): abstract P-M-664.
57. Frost C, Yu Z, Nepal S, et al. Apixaban, a direct Factor Xa inhibitor: single-dose pharmacokinetics and pharmacodynamics of an intravenous formulation [abstract no. 142]. J Clin Pharmacol 2008;48:1132.
58. Wang L, He K, Maxwell B, et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos. 2011;39(2):256-64.
59. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-98.
60. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604.
61. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92.
62. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-17.
63. Frost CE YZ, Wang J, Li C, Zeigler C, Schuster A, Ly V, Zhang D, LaCreta F. Single-dose safety and pharmacokinetics of apixaban in subjects with mild or moderate hepatic impairment. Clin Pharmacol Ther 2009; 85 (Suppl.1): S34 (PI-84).
64. Mendell J JL, Ridout G, He L, Chen S. An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics [abstract]. Eur Heart J 2012; 33 (Suppl 1): abstract 2024.
65. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011;123(13):1436-50.
66. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292-303.
67. Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47(1):47-59.
68. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259-68.
69. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370(9591):949- 56.
70. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*): a randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-9.
71. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51.
72. Bayer Pharma AG. Xarelto® (rivaroxaban) aummary of product characteristics. 2012. http://www.xarelto.com/html/downloads/Xarelto- Prescribing-Information-May-2012.pdf. Accessed 31 Jul 2012.
73. Bristol-Myers Squibb PE. Eliquis (apixaban) summary of product characteristics. 2011. http://www.eliquis.com/PDF/ELIQUIS%20%20(apixaban) %20SmPC.pdf. Accessed 31 Jul 2012.
74. Boehringer Ingelheim IG. Pradaxa (dabigatran etexilate) summary of product characteristics. 2011. http://www.ema.europa.eu/docs/en-GB/document- library/EPAR-Product-Information/human/000829/WC500041059.pdf. Accessed 31 Jul 2012.
75. DAIICHI S. LIXIANA® (edoxaban). http://www.daiichisankyo.com/news/ detail/004123.html. Accessed 15 Jan 2013.
76. Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate) prescribing information. 2012. http://www.accessdata.fda.gov/drugsatfda-docs/ label/2012/022512s010lbl.pdf. Accessed 31 Jul 2012.
77. Janssen Pharmaceuticals, Inc. Xarelto® (rivaroxaban) prescribing information. 2011. http://www.accessdata.fda.gov/drugsatfda-docs/label/2011/ 202439s001lbl.pdf. Accessed 31 Jul 2012.
78. Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother. 2012;46(4):e10.
79. Cano EL, Miyares MA. Clinical challenges in a patient with dabigatran-induced fatal hemorrhage. Am J Geriatr Pharmacother. 2012;10(2):160-3.
80. Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med. 2011;49(5):761-72.
81. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl 1):S141-5.
82. van Ryn J SP, Kink-Eiband M, Gansser D, Clemens A. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro [abstract no. 1065]. 51st American Society of Hematology Annual Meeting and Exposition; 5-9 Dec 2009; New Orleans.
83. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573-9.
84. Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost. 2010;103(3):572-85.
85. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41-57.