Download PDF
Thromb Haemost 2017; 117(11): 2026-2033
DOI: 10.1160/TH16-10-0815
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease

Detlef Albrecht
,
Mintu P. Turakhia
,
Daniel Ries
,
Thomas Marbury
,
William Smith
,
Debbie Dillon
,
Peter G. Milner
,
Mark G. Midei
Further Information

Publication History

28 October 2016

16 June 2017

Publication Date:
30 November 2017 (online)

Also available at
    Permissions and Reprints

Abstract

Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t 1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.

Keywords

tecarfarin - warfarin - vitamin K antagonist - Chronic kidney disease - pharmacokinetics

Supplementary Material

 

  • References

  • 1 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39 (02) (Suppl. 01) S1-S266
    PubMedGoogle Scholar
  • 2 Eckardt KU, Coresh J, Devuyst O. , et al. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 2013; 382 (9887): 158-169
    CrossrefPubMedGoogle Scholar
  • 3 Boriani G, Savelieva I, Dan GA. , et al; Document reviewers. Chronic kidney disease in patients with cardiac rhythm disturbances or implantable electrical devices: clinical significance and implications for decision making-a position paper of the European Heart Rhythm Association endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society. Europace 2015; 17 (08) 1169-1196
    CrossrefPubMedGoogle Scholar
  • 4 Weiner DE. Public health consequences of chronic kidney disease. Clin Pharmacol Ther 2009; 86 (05) 566-569
    CrossrefPubMedGoogle Scholar
  • 5 Go AS, Fang MC, Udaltsova N. , et al; ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119 (10) 1363-1369
    CrossrefPubMedGoogle Scholar
  • 6 Turakhia MP, Santangeli P, Winkelmayer WC. , et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol 2014; 64 (07) 660-668
    CrossrefPubMedGoogle Scholar
  • 7 Carrero JJ, Evans M, Szummer K. , et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311 (09) 919-928
    CrossrefPubMedGoogle Scholar
  • 8 Jun M, James MT, Manns BJ. , et al; Alberta Kidney Disease Network. The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study. BMJ 2015; 350: h246
    CrossrefPubMedGoogle Scholar
  • 9 Goldstein BA, Arce CM, Hlatky MA, Turakhia M, Setoguchi S, Winkelmayer WC. Trends in the incidence of atrial fibrillation in older patients initiating dialysis in the United States. Circulation 2012; 126 (19) 2293-2301
    CrossrefPubMedGoogle Scholar
  • 10 Providência R, Marijon E, Boveda S. , et al. Meta-analysis of the influence of chronic kidney disease on the risk of thromboembolism among patients with nonvalvular atrial fibrillation. Am J Cardiol 2014; 114 (04) 646-653
    CrossrefPubMedGoogle Scholar
  • 11 Friberg L, Benson L, Lip GYH. Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study. Eur Heart J 2015; 36 (05) 297-306
    CrossrefPubMedGoogle Scholar
  • 12 Apostolakis S, Guo Y, Lane DA, Buller H, Lip GY. Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial. Eur Heart J 2013; 34 (46) 3572-3579
    CrossrefPubMedGoogle Scholar
  • 13 Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010; 137 (02) 263-272
    CrossrefPubMedGoogle Scholar
  • 14 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138 (05) 1093-1100
    CrossrefPubMedGoogle Scholar
  • 15 Yeung CK, Shen DD, Thummel KE, Himmelfarb J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int 2014; 85 (03) 522-528
    CrossrefPubMedGoogle Scholar
  • 16 Ladda MA, Goralski KB. The effects of CKD on cytochrome P450–mediated drug metabolism. Adv Chronic Kidney Dis 2016; 23 (02) 67-75
    CrossrefPubMedGoogle Scholar
  • 17 Limdi NA, Limdi MA, Cavallari L. , et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010; 56 (05) 823-831
    CrossrefPubMedGoogle Scholar
  • 18 Bonde AN, Lip GYH, Kamper A-L. , et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64 (23) 2471-2482
    CrossrefPubMedGoogle Scholar
  • 19 Chan KE, Giugliano RP, Patel MR. , et al. Nonvitamin K anticoagulant agents in patients with advanced chronic kidney disease or on dialysis with AF. J Am Coll Cardiol 2016; 67 (24) 2888-2899
    CrossrefPubMedGoogle Scholar
  • 20 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedGoogle Scholar
  • 21 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedGoogle Scholar
  • 22 Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol 2011; 6 (11) 2599-2604
    CrossrefPubMedGoogle Scholar
  • 23 January CT, Wann LS, Alpert JS. , et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64 (21) e1-e76
    CrossrefPubMedGoogle Scholar
  • 24 Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73 (01) 67-74
    CrossrefPubMedGoogle Scholar
  • 25 Holbrook AM, Pereira JA, Labiris R. , et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10) 1095-1106
    CrossrefPubMedGoogle Scholar
  • 26 Santos PCJL, Dinardo CL, Schettert IT. , et al. CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability in patients on long-term anticoagulation. Eur J Clin Pharmacol 2013; 69 (04) 789-797
    CrossrefPubMedGoogle Scholar
  • 27 Yang J, Chen Y, Li X. , et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013; 168 (04) 4234-4243
    CrossrefPubMedGoogle Scholar
  • 28 Bachmann K, Shapiro R, Mackiewicz J. Warfarin elimination and responsiveness in patients with renal dysfunction. J Clin Pharmacol 1977; 17 (5–6): 292-299
    CrossrefPubMedGoogle Scholar
  • 29 White PJ. Patient factors that influence warfarin dose response. J Pharm Pract 2010; 23 (03) 194-204
    CrossrefPubMedGoogle Scholar
  • 30 Kleinow ME, Garwood CL, Clemente JL, Whittaker P. Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic. J Manag Care Pharm 2011; 17 (07) 523-530
    CrossrefPubMedGoogle Scholar
  • 31 Kooiman J, van Rein N, Spaans B. , et al. Efficacy and safety of vitamin K-antagonists (VKA) for atrial fibrillation in non-dialysis dependent chronic kidney disease. PLoS One 2014; 9 (05) e94420
    CrossrefPubMedGoogle Scholar
  • 32 Proietti M, Lane DA, Lip GY. Chronic kidney disease, time in therapeutic range and adverse clinical outcomes in anticoagulated patients with non-valvular atrial fibrillation: observations from the SPORTIF trials. EBioMedicine 2016; 8: 309-316
    CrossrefPubMedGoogle Scholar
  • 33 Beton O, Asarcikli LD, Sen T. , et al. Right ventricular dysfunction complicates time in therapeutic range in heart failure patients receiving warfarin. Pharmacology 2017; 99 (1–2): 19-26
    CrossrefPubMedGoogle Scholar
  • 34 Yang F, Hellyer JA, Than C. , et al. Warfarin utilisation and anticoagulation control in patients with atrial fibrillation and chronic kidney disease. Heart 2017; 103 (11) 818-826
    CrossrefPubMedGoogle Scholar
  • 35 Albrecht D, Ellis D, Canafax DM. , et al. Pharmacokinetics and pharmacodynamics of tecarfarin, a novel vitamin K antagonist oral anticoagulant. Thromb Haemost 2017; 117 (04) 706-717
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Bavisotto LM, Ellis DJ, Milner PG, Combs DL, Irwin I, Canafax DM. Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants. J Clin Pharmacol 2011; 51 (04) 561-574
    CrossrefPubMedGoogle Scholar
  • 37 Whitlock RP, Fordyce CB, Midei MG. , et al. A randomised, double blind comparison of tecarfarin, a novel vitamin K antagonist, with warfarin. The EmbraceAC Trial. Thromb Haemost 2016; 116 (02) 241-250
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e44S-e88S
    CrossrefPubMedGoogle Scholar
  • 39 Jones DR, Kim SY, Guderyon M, Yun CH, Moran JH, Miller GP. Hydroxywarfarin metabolites potently inhibit CYP2C9 metabolism of S-warfarin. Chem Res Toxicol 2010; 23 (05) 939-945
    CrossrefPubMedGoogle Scholar
  • 40 Maddison J, Somogyi AA, Jensen BP, James HM, Gentgall M, Rolan PE. The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype. Br J Clin Pharmacol 2013; 75 (01) 208-216
    CrossrefPubMedGoogle Scholar
  • 41 Wittkowsky AK. Warfarin (AHFS 20:12.04). In: Murphy JE. , ed. Clinical Pharmacokinetics. 5th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2012: 351-372
    Google Scholar
  • 42 Ohara M, Takahashi H, Lee MTM. , et al. Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses. PLoS One 2014; 9 (08) e105891
    CrossrefPubMedGoogle Scholar
  • 43 Belley-Cote EP, Hanif H, D'Aragon F. , et al. Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation. A systematic review and meta-analysis. Thromb Haemost 2015; 114 (04) 768-777
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Gong IY, Schwarz UI, Crown N. , et al. Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation. PLoS One 2011; 6 (11) e27808
    CrossrefPubMedGoogle Scholar
  • 45 Alshogran OY. Characterization of the Effects of the Chronic Kidney Disease on Hepatic Reduction: In-Vitro and In-Vivo Studies of Warfarin [dissertation]. Pittsburgh, PA: University of Pittsburgh; 2014
    Google Scholar
  • 46 Dreisbach AW, Japa S, Gebrekal AB. , et al. Cytochrome P4502C9 activity in end-stage renal disease. Clin Pharmacol Ther 2003; 73 (05) 475-477
    PubMedGoogle Scholar
  • 47 Henne KR, Gaedigk A, Gupta G, Leeder JS, Rettie AE. Chiral phase analysis of warfarin enantiomers in patient plasma in relation to CYP2C9 genotype. J Chromatogr B Biomed Sci Appl 1998; 710 (1–2): 143-148
    CrossrefPubMedGoogle Scholar
  • 48 Momper JD, Venkataramanan R, Nolin TD. Nonrenal drug clearance in CKD: Searching for the path less traveled. Adv Chronic Kidney Dis 2010; 17 (05) 384-391
    CrossrefPubMedGoogle Scholar
  • 49 Ellis DJ, Usman MH, Milner PG, Canafax DM, Ezekowitz MD. The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation. Circulation 2009; 120 (12) 1029-1035 , 2, 1035
    CrossrefPubMedGoogle Scholar