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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2016

Open Access 01-06-2016 | Review Article

Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa

Authors: Dolly A. Parasrampuria, Kenneth E. Truitt

Published in: Clinical Pharmacokinetics | Issue 6/2016

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Abstract

Edoxaban, a once daily non-vitamin K antagonist oral anticoagulant, is a direct, selective, reversible inhibitor of factor Xa (FXa). In healthy subjects, single oral doses of edoxaban result in peak plasma concentrations within 1.0–2.0 h of administration, followed by a biphasic decline. Exposure is approximately dose proportional for once daily doses of 15–150 mg. Edoxaban is predominantly absorbed from the upper gastrointestinal tract, and oral bioavailability is approximately 62 %. Food does not affect total exposure to edoxaban. The terminal elimination half-life in healthy subjects ranges from 10 to 14 h, with minimal accumulation upon repeat once daily dosing up to doses of 120 mg. The steady-state volume of distribution is approximately 107 L, and total clearance is approximately 22 L/h; renal clearance accounts for approximately 50 % of total clearance, while metabolism and biliary secretion account for the remaining 50 %. Intrinsic factors, such as age, sex and race, do not affect edoxaban pharmacokinetics after renal function is taken into account. Oral administration of edoxaban results in rapid changes in anticoagulatory biomarkers, with peak effects on anticoagulation markers (such as anti-FXa), the prothrombin time and the activated partial thromboplastin time occurring within 1–2 h of dosing.
Literature
1.
Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e419S–94S.CrossRefPubMedPubMedCentral
2.
Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719–47.CrossRefPubMed
3.
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):2071–104.CrossRefPubMed
4.
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl):160S–98S.CrossRefPubMed
5.
Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med. 1994;121(9):676–83.CrossRefPubMed
6.
Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost. 2008;6(9):1542–9.PubMed
7.
Matsushima N, Lee F, Sato T, Weiss D, Mendell J. Bioavailability and safety of the factor Xa inhibitor edoxaban and the effects of quinidine in healthy subjects. Clin Pharm Drug Dev. 2013;2:358–66.CrossRef
8.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104.CrossRefPubMed
9.
The Hokusai VTE Investigators, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.
10.
Lixiana® (edoxaban tosilate hydrate tablets): full prescribing information. Tokyo: Daiichi Sankyo Company, Ltd.; 2014.
11.
Savaysa™ (edoxaban) tablets for oral use: full prescribing information. Parsippany: Daiichi Sankyo Inc.; 2015.
12.
13.
Lixiana® (edoxaban): package leaflet. Munich: Daiichi Sankyo Europe GmbH; 2015.
14.
Fuji T, Fujita S, Kawai Y, Nakamura M, Kimura T, Kiuchi Y, et al. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res. 2014;133(6):1016–22.CrossRefPubMed
15.
Fuji T, Wang CJ, Fujita S, Kawai Y, Kimura T, Tachibana S. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan. J Arthroplasty. 2014;29(12):2439–46.CrossRefPubMed
16.
Fuji T, Fujita S, Kawai Y, Nakamura M, Kimura T, Fukuzawa M, et al. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V. Thromb J. 2015;13:27.CrossRefPubMedPubMedCentral
17.
18.
Mikkaichi T, Yoshigae Y, Masumoto H, Imaoka T, Rozehnal V, Fischer T, et al. Edoxaban transport via P-glycoprotein is a key factor for the drug’s disposition. Drug Metab Dispos. 2014;42(4):520–8.CrossRefPubMed
19.
Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.CrossRefPubMed
20.
Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50(7):743–53.CrossRefPubMed
21.
Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos. 2012;40(12):2250–5.CrossRefPubMed
22.
Parasrampuria D, Weilert J, Maa J, He L, Shi M, Brown K. Pharmacokinetics (PK) of edoxaban, a novel oral anticoagulant (NOAC), when dosed alone or following switching from dabigatran or rivaroxaban. Clin Pharmacol Ther. 2014;95(Suppl 1):S83.
23.
Parasrampuria DA, Kanamaru T, Connor A, Wilding I, Ogata K, Shimoto Y, et al. Evaluation of regional gastrointestinal absorption of edoxaban using the enterion capsule. J Clin Pharmacol. 2015 [Epub ahead of print].
24.
Mendell J, Tachibana M, Shi M, Kunitada S. Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. J Clin Pharmacol. 2011;51(5):687–94.CrossRefPubMed
25.
Yin OQ, Miller R. Population pharmacokinetics and dose–exposure proportionality of edoxaban in healthy volunteers. Clin Drug Investig. 2014;34(10):743–52.CrossRefPubMed
26.
Masumoto H, Yoshigae Y, Watanabe K, Takakusa H, Okazaki O, Izumi T. In vitro metabolism of edoxaban and the enzymes involved in the oxidative metabolism of edoxaban. AAPS J. 2010;12 (Suppl 2):Abstract W4308.
27.
Ogura Y, Masumoto H, Yoshigae Y, Kosaka T, Shinagawa A. Identification of human hydrolase involved in the metabolism of edoxaban to a human major metabolite. AAPS J. 2010;12:Abstract W4298.
28.
Jonsson S, Simonsson US, Miller R, Karlsson MO. Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study. J Clin Pharmacol. 2015 May 12 [Epub ahead of print].
29.
Vandell A, Lee J, Shi M, Rubets I, Brown K, Walker JR. Lack of an affect of the ABCB1 C3435T (RS104564) polymorphism on the pharmacokinetics of edoxaban, a novel factor Xa inhibitor. Clin Pharmacol Therap. 2014;95(Suppl 1):S74.
30.
Mendell J, Shi M. Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of edoxaban in healthy post-menopausal or surgically sterile females, and healthy elderly males. Eur Heart J. 2011;32(Suppl 1):461.
31.
Ridout G, de la Motte S, Niemczyk S, Sramek P, Johnson L, Jin J, et al. effect of renal function on edoxaban pharmacokinetics and on population PK model. J Clin Pharmacol. 2009;49:1091–130 (Abstract 144).
32.
Mendell J, Johnson L, Chen S. An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 2015 May 22 [Epub ahead of print].
33.
Yin OQ, Tetsuya K, Miller R. Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation. Eur J Clin Pharmacol. 2014;70(11):1339–51.CrossRefPubMed
34.
Zahir H, Mendell J, Jin J, He L, Parasrampuria DA. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of edoxaban in healthy adults. Clin Pharm Drug Dev. 2014;(Suppl 1):1–59.
35.
36.
37.
Mendell J, Zahir H, Matsushima N, Noveck R, Lee F, Chen S, et al. Drug–drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs. 2013;13(5):331–42.CrossRefPubMedPubMedCentral
38.
Mendell J, Zhang G, He L, Parasrampuria DA. The effects of erythromycin on the pharmacokinetics and pharmacodynamics of edoxaban. Clin Pharmacol Drug Dev. 2014;3(Suppl 1):1–59.
39.
Matsushima N, Zahir H, Mendell J, Chen S, He L, Parasrampuria DA. Coadministration of cyclosporine increased edoxaban exposure in healthy adults. Clin Pharmacol Drug Dev. 2014;3(Suppl 1):1–59.
40.
41.
Robinson K, Johnston A, Walker S, Mulrow JP, McKenna WJ, Holt DW. The digoxin–amiodarone interaction. Cardiovasc Drugs Ther. 1989;3(1):25–8.CrossRefPubMed
42.
Mendell J, Chen S, He L, Desai M, Parasramupria DA. The effect of rifampin on the pharmacokinetics of edoxaban in healthy adults. Clin Drug Investig. 2015;35(7):447–53.CrossRefPubMedPubMedCentral
43.
Mendell J, Lee F, Chen S, Worland V, Shi M, Samama MM. The effects of the antiplatelet agents, aspirin and naproxen, on pharmacokinetics and pharmacodynamics of the anticoagulant edoxaban, a direct factor Xa inhibitor. J Cardiovasc Pharmacol. 2013;62(2):212–21.CrossRefPubMed
44.
Zahir H, Matsushima N, Halim AB, He L, Zhang G, Lee F, et al. Edoxaban administration following enoxaparin: a pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects. Thromb Haemost. 2012;108(1):166–75.CrossRefPubMed
45.
Mendell J, Lasseter K, Shi M. Effect of esomeprazole on edoxaban pharmacokinetics and pharmacodynamics when administered orally as tablet and as solution. Eur J. 2011;13 (Suppl 3):Abstract P1052.
46.
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.CrossRefPubMed
47.
Song S, Kang D, Halim AB, Miller R. Population pharmacokinetic–pharmacodynamic modeling analysis of intrinsic FXa and bleeding from edoxaban treatment. J Clin Pharmacol. 2014;54(8):910–6.CrossRefPubMed
48.
Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost. 2010;104(3):633–41.CrossRefPubMed
49.
Salazar DE, Mendell J, Kastrissios H, Green M, Carrothers TJ, Song S, et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost. 2012;107(5):925–36.CrossRefPubMed
50.
Zafar MU, Vorchheimer DA, Gaztanaga J, Velez M, Yadegar D, Moreno PR, et al. Antithrombotic effects of factor Xa inhibition with DU-176b: phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost. 2007;98(4):883–8.PubMed
51.
Wolzt M, Samama MM, Kapiotis S, Ogata K, Mendell J, Kunitada S. Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux. Thromb Haemost. 2011;105(6):1080–90.CrossRefPubMed
52.
Samama MM, Kunitada S, Oursin A, Depasse F, Heptinstall S. Comparison of a direct factor Xa inhibitor, edoxaban, with dalteparin and ximelagatran: a randomised controlled trial in healthy elderly adults. Thromb Res. 2010;126(4):e286–93.CrossRefPubMed
53.
Parasrampuria DA, Weilert D, Maa J-F, Dishy V, Kochan J, Shi M, et al. Switching from dabigatran or rivaroxaban to edoxaban: a biomarker assessment in healthy subjects. Thromb Haemost. 2014;12(Suppl 1): 1–106 (Abstract COA41).
54.
55.
Mendell J, Basavapathruni R, Swearingen D, Draves A, Zhang G, Morganroth J. A thorough electrocardiogram study of edoxaban, a novel factor Xa inhibitor. J Clin Pharmacol. 2011;51(8):1241–6.CrossRefPubMed
56.
Mendell J, Noveck RJ, Shi M. A randomized trial of the safety, pharmacokinetics and pharmacodynamics of edoxaban, an oral factor Xa inhibitor, following a switch from warfarin. Br J Clin Pharmacol. 2013;75(4):966–78.CrossRefPubMedPubMedCentral
57.
Ruff CT, Giugliano RP, Braunwald E, Mercuri M, Curt V, Betcher J, et al. Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF–TIMI 48 trial. J Am Coll Cardiol. 2014;64(6):576–84.CrossRefPubMed
Metadata
Title
Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa
Authors
Dolly A. Parasrampuria
Kenneth E. Truitt
Publication date
01-06-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0342-7

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