Edoxaban, LC/MS

CPT: 80299
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Test Details

Synonyms

  • Savaysa®

Use

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 to10 days of initial anticoagulant therapy.2,3

Methodology

Liquid chromatography/tandem mass spectrometry (LC/MS-MS)

Additional Information

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 as long as 24 hours.4,5,8,9 Edoxaban 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 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 (ie, 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 of aspirin (325 mg/day), and strong P-glycoprotein inhibitors (ritonavir and cyclosporine) increase edoxaban steady-state plasma concentrations.10,16

Once absorbed, edoxaban undergoes biotransformation to various metabolites, some of which are active, 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.5 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. Measurement of levels can inform clinicians with concerns regarding patient compliance and adherence to therapy. 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. 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 affect on the recovery of drug.

Specimen Requirements

Specimen

Plasma

Volume

0.5 mL

Minimum Volume

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

Container

Green-top (heparin) tube (preferred) or blue-top (sodium citrate) tube

Collection

Transfer plasma to a plastic transport tube.

Storage Instructions

Room temperature

Stability Requirements

Temperature

Period

Room temperature

7 days

Refrigerated

14 days

Frozen

14 days

Freeze/thaw cycles

Stable x3

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. Available at: http://www.xarelto-us.com/. Accessed April 10 2015.
3. Xarelto® Prescribing Information (Revised December 2011). Available at: http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100. Accessed April 10 2015.
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 of 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; 2(4):358-366.
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 drugs 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. 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 Jun 1; 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 Xa 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 J Med. 2013 Nov 28; 369(22):2093-2104. 24251359

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
117060 Edoxaban by LCMS 82468-0 117059 Edoxaban by LCMS ng/mL 82468-0

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