Dabigatran

CPT: 80375
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Test Details

Synonyms

  • Pradaxa® (Dabigatran Etexilate)

Use

Measurement of drug level in order to monitor therapeutic level and/or diagnose under-dosage or potential toxicity.

Limitations

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

Methodology

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

Additional Information

Dabigatran etexilate mesylate (Pradaxa®) is a selective, reversible, direct thrombin inhibitor that has been approved for thromboprophylaxis to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1-4 Dabigatran etexilate is a prodrug that is administered orally and has a bioavailability of 6.5%. After absorption into the bloodstream, the prodrug is converted by ubiquitous esterases to the active drug, dabigatran. Approximately one third of circulating dabigatran is bound to plasma proteins.5 Maximum serum concentrations are reached between 1.5 and 3 hours after dosing.6,7 Pharmacokinetic studies reveal an interindividual coefficient of variation of approximately 30%.6 Dabigatran is widely distributed through the bloodstream but does not cross the blood-brain barrier to an appreciable extent.8 Repeated administration in patients with normal renal function is 14 to 17 hours permitting a once daily administration of the drug.6

Approximately 80% of the dabigatran in the blood is eliminated unchanged through renal excretion.9 As a consequence, there is a risk of drug accumulation in patients with renal impairment.4,10 Renal function should be evaluated before prescribing dabigatran.11,12 The FDA-approved 150-mg twice-daily dabigatran for patients with normal renal function and 75-mg twice-daily for patients with impaired renal function (ie, a creatinine clearance 20 to 50 mL/minute). Renal function should be assessed on a regular basis in situations in which decline anticipated and at least yearly for patients older than 75. Because dabigatran is not metabolized by cytochrome P450 isoenzymes, it has few major interactions with other drugs;9 however, drugs that either induce or inhibit P-glycoprotein can affect the absorption of the drug in the gut.9

There is no reversal agent for dabigatran, although hemodialysis can be employed for rapid removal of the drug in life-threatening circumstances.13 A procoagulant, such as recombinant-activated factor VII, can also be employed in the management of severe bleeding associated with dabigatran.13

Routine therapeutic monitoring of dabigatran levels is not required because of the drug's relatively wide therapeutic index. Despite the use of fixed doses of dabigatran, 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.14 Dabigatran 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 dabigatran, respectively.4 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 or hepatic failure and when administered with other drugs that may alter metabolism or clearance. Total dabigatran, ie, the sum of dabigatran and its pharmacologically active glucuronides,15 is measured after complete alkaline cleavage of the glucuronide conjugates present in the samples using a validated liquid chromatography/mass spectrometry (LC/MS-MS) method. Use of liquid LC/MS-MS provides highly accurate measurement of dabigatran concentrations without the variable interferences associated with traditional clot-based and chromogenic assays.16,17 In fact, studies performed using the LabCorp LC/MS-MS method indicate 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.

Specimen Requirements

Specimen

Plasma

Volume

1 mL

Minimum Volume

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

Container

Blue-top (sodium citrate) tube (preferred), lavender-top (EDTA) tube, or green-top (heparin) 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. FDA Approves Pradaxa to Prevent Stroke in People with Atrial Fibrillation. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm accessed March 30, 2012.
2. Harenberg J, Giese C, Marx S, Krämer R. Determination of dabigatran in human plasma samples. Semin Thromb Hemost. 2012 Feb; 38(1):16-22. 22314599
3. Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost. 2010 Mar;103(3):572-585. 20135071
4. Huisman MV, Lip GY, Diener HC, Brueckmann M, van Ryn J, Clemens A. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: Resolving uncertainties in routine practice. Thromb Haemost. 2012 May 2;107(5):838-847. 22318514
5. 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 Feb; 36(2):386-399. 18006647
6. Stangier J, Rathgen K, Stähle 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 Sep; 64(3):292-303. 17506785
7. Stangier J, Stähle 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. 18076218
8. Bovio JA, Smith SM, Gums JG. Dabigatran etexilate: A novel oral thrombin inhibitor for thromboembolic disease. Ann Pharmacother. 2011 May; 45(5):603-614. 21540406
9. Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009 Sep-Oct; 15(Suppl 1):9S-16S. 19696042
10. Stangier J, Rathgen K, Stähle 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 Apr 1; 49(4):259-268. 20214409
11. Schulman S, Kearon C, Kakkar AK, et al; "RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10; 361(24):2342-2352. 19966341
12. 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 Sep 17; 361(12):1139-1151. 19717844
13. Augoustides JG. Advances in anticoagulation: Focus on dabigatran, an oral direct thrombin inhibitor. J Cardiothorac Vasc Anesth. 2011 Dec; 25(6):1208-1212. 21982327
14. Schulman S, Majeed A. The oral thrombin inhibitor dabigatran: Strengths and weaknesses. Semin Thromb Hemost. 2012 Feb; 38(1):7-15. 22314598
15. Ebner T, Wagner K, Wienen W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep; 38(9):1567-1575. 20551237
16. Lindahl TL, Baghaei F, Blixter IF, et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost. 2011 Feb; 105(2):371-378. 21103660
17. Freyburger G, Macouillard G, Labrouche S, Sztark F. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: Two observational studies in patients undergoing total hip or total knee replacement. Thromb Res. 2011 May; 127(5):457-465. 21277622

References

Adcock DM, Gosselin R, Kitchen S, Dwyre DM. The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol. 2013 Jan; 139(1):102-109. 23270905
Härtter S, Yamamura N, Stangier J, Reilly PA, Clemens A. Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate. Thromb Haemost. 2012 Feb;107(2):260-269. 22186806
van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010 Jun; 103(6):1116-1127. 20352166

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
117076 Dabigatran 72625-7 117077 Dabigatran ng/mL 72625-7
Reflex Table for Dabigatran
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 123244 Disclaimer: 123244 Disclaimer: N/A

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