Edoxaban, Anti-Xa

CPT: 85130
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Test Details

Synonyms

  • Savaysa®

Use

Measure plasma edoxaban concentration in ng/mL. Although routine monitoring is not needed, there are several clinical circumstances in which clinicians want or need to know a patient's edoxaban level. Levels can be accurately and precisely measured using either a chromogenic anti-Xa assay or LC/MS-MS.

Limitations

This assay is not specific for edoxaban and will measure any direct or indirect factor Xa anticoagulant.

This test was developed, and its performance characteristics determined, by LabCorp. It has not been cleared by the US Food and Drug Administration (FDA).

Methodology

Chromogenic anti-Xa. Edoxaban inhibition of factor Xa (present in excess). Residual Xa is measured using a chromogen and is inversely proportional to the edoxaban present.

Additional Information

Edoxaban (Savaysa®) is an oral anticoagulant that impairs thrombin generation by inhibiting factor Xa produced as the result of both the intrinsic and extrinsic coagulation pathways. 1 This small molecular weight drug inhibits free, prothrombinase-bound and clot-associated factor Xa in a concentration-dependent manner.1 The product labeling from January 2015 approves the use of edoxaban for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the treatment of deep vein thrombosis (DVT), which may lead to pulmonary embolism following 5 to 10 days of initial anticoagulant therapy.2,3 Edoxaban has been shown to exhibit dose-dependent anti-FXa activity with predictable pharmacokinetic and pharmacodynamic profiles.4-7 The time to maximum plasma concentration has been estimated to be one to two hours following administration, and drug levels have been shown to remain above baseline levels for 24 hours.4,5,8,9 Edoxaben has a half-life of approximately 10 to 14 hours, and its absolute oral bioavailability is 62% in healthy subjects.7,10,11 Edoxaban distributes to extravascular tissues with relatively low protein binding (40% to 59%).9 Food intake, ethnicity, and gender have no influence on edoxaban absorption, elimination, maximum concentration, half-life, or antifactor Xa activity.12,13

Edoxaban is a substrate of for the efflux transporter P-glycoprotein, which acts to pump drugs back into the intestinal lumen, thereby limiting systemic absorption.10,13,14 For this reason, a dose reduction is recommended when edoxaban is coadministered with strong P-glycoprotein inhibitors, including quinidine, verapamil, and dronedarone.15 However, coadministration with other P-glycoprotein substrates (eg, atorvastatin or digoxin) has only minor effects on the pharmacokinetics of edoxaban.10 Certain macrolide antibiotics (erythromycin, azithromycin, and clarithromycin), azole antifungals (ketoconazole and itraconazole), high-dose aspirin (325 mg/day), and strong P-glycoprotein (ritonavir and cyclosporine) increase edoxaban steady-state plasma concentrations.10,16 Once absorbed, edoxaban undergoes biotransformation to various metabolites, some of which are active and the most abundant of which (M4) is formed through hydrolysis.9 Elimination occurs via the kidneys at a rate higher than glomerular filtration, suggesting active secretion into the kidney. The renal elimination of edoxaban has been estimated to be from 35%5,9 to 50% in healthy volunteers.7 Administration of lower doses of once-daily edoxaban may be necessary in patients with renal impairment. Routine therapeutic monitoring of edoxaban level is not required because of the drug's relatively wide therapeutic index. Despite the use of fixed doses of edoxaban, determination of the amount of drug present in a given individual may be valuable in several clinical situations, such as patients who experience bleeding or treatment failure.17,18 Determination of drug concentration may also be needed in patients who require thrombolytic therapy, surgery, or who have suffered trauma. It may also be of value in those with renal insufficiency, advanced age, and low body weight.17,18

Measurement of levels can inform clinicians with concerns regarding patient compliance and adherence to therapy as well as in situations of suspected or known overdose. Edoxaban is transported across the intestinal wall by P-glycoprotein and drugs that induce or inhibit P-glycoprotein activity, may decrease or increase the levels of edoxaban, respectively. Therapeutic monitoring can help the clinician assess the potential cause of bleeding or thrombosis while on therapy. Determination of levels may also be useful in preparation for surgery or an invasive procedure. Also, drug level measurement can be valuable in determining drug accumulation in situations of renal failure and when administered with other drugs that may alter metabolism or clearance. Edoxaban can be measured using a validated liquid chromatography-mass spectrometry (HPLC/MS-MS) method as well as a validated chromogenic anti-Xa method. Use of liquid LC/MS-MS provides highly accurate measurement of edoxaban concentrations without the variable interferences associated with traditional clot-based and chromogenic assays.13 In fact, studies performed using the LabCorp LC/MS-MS method indicate that the assayed drug recovery was unaffected by the presence of lupus anticoagulants or heparin administration. Factor VIII deficiency and multiple factor deficiency associated with coumadin treatment had no effect on the recovery of drug. A chromogenic anti-Xa assay can accurately determine edoxaban concentration in plasma, although this assay is not specific for edoxaban and will detect any anti-Xa anticoagulant, both direct and indirect.18

Specimen Requirements

Specimen

Plasma, frozen

Volume

1 mL

Minimum Volume

0.5 mL (Note: This volume does not allow for repeat testing.)

Container

Blue-top (3.2% sodium citrate) tube

Collection

Separate plasma from cells by centrifugation. Transfer plasma to a plastic transport tube before freezing.

Storage Instructions

Freeze. Stable at room temperature for six hours. Freeze/thaw cycles: x5.

Causes for Rejection

Gross hemolysis; gross lipemia

Clinical Information

Footnotes

1. Camm AJ, Bounameaux H. Edoxaban: A new oral direct factor Xa inhibitor. Drugs. 2011 Aug 20; 71(12):1503-1526. 21861537
2. Xarelto® (Rivaroxaban) Official Site. (03/15/2012). http://www.xarelto-us.com/ Accessed April 10 2015.
3. Xarelto® Prescribing Information [package insert] Revised December 2011.
4. Zafar MU, Vorchheimer DA, Gaztanaga J, 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 Oct; 98(4):883-888. 17938815
5. Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010 Jul; 50(7):743-753. 20081065
6. Furugohri T, Isobe K, Honda Y, et al. DU-176b, A potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost. 2008 Sep; 6(9):1542-1549. 18624979
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 Oct;2(4):358-366. 27121940
8. Zahir H, Matsushima N, Halim AB, et al. Edoxaban administration following enoxaparin: A pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects. Thromb Haemost. 2012 Jul;108(1):166-175. 22628060
9. 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 Dec; 40(12):2250-2255. 22936313
10. Mendell J, Zahir H, Matsushima N, et al. Drug-drug interaction studies of cardiovascular drug involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs. 2013 Oct;13(5):331-342. 23784266
11. Mendell J, Lee F, Chen S, Worland V, Shi M, Samama M, et al. The effects of the antiplatelet agents, aspirin and naproxen, on pharmacokinetics and pharmacodynamics of the anticoagulant edoxaban, a direct factor Xa inhibitor. J Cardiovas Pharmacol. 2013 Aug; 62(2):212-221. 23615159
12. Mendell J, Chen S, He L, Parasrampuria D. The effect of rifampin on the PK and PD of edoxaban in healthy subjects. J Thromb Haemost. 2014;12(Suppl 1):17.
13. Mendell J, Tachibana M, Shi M, Kunitada S. Effects of food on the pharmacokinetics of edoxaban, an oral direct factor X inhibitor, in healthy volunteers. J Clin Pharmacol. 2011 May; 51(5):687-694. 20534818
14. Mikkaichi T, Yoshigae Y, Masumoto H, et al. Edoxaban transport via P-glycoprotein is a key factor for the drug's disposition. Drug Metab Dispos. 2014 Apr;42(4):520-528. 24459178
15. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the effective anticoagulation with factor Xa next Generation in atrial fibrillation-thrombolysis in myocardial infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010 Oct;160(4):635-641. 20934556
16. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl Med. 2013 Nov 28; 369(22):2093-2104. 24251359
17. Cuker A. Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J Thromb Thrombolysis. 2016 Feb; 41(2):241-247. 26386967
18. García D, Barrett YC, Ramacciotti, Weitz JI. Laboratory assessment of anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemostasis. 2013 Feb; 11(2):245-252. 23216682

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
504430 Edoxaban Anti Xa 80627-3 504431 Edoxaban Anti Xa ng/mL 80627-3
504430 Edoxaban Anti Xa 80627-3 504432 Edoxaban Anti Xa N/A

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