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aPTT in rats and in humans ex vivo.18,19 In a punch biopsy study with 110 healthy volunteers, 4-factor PCC (Beriplex®


)


showed a dose-dependent reversal of edoxaban 60mg with complete reversal of bleeding duration following 50IU/kg.20 PER977, a small molecule capable of binding to both heparin and NOACs, rapidly reversed the anticoagulant effects of edoxaban, as well as of other factor Xa inhibitors, in vitro and was successfully evaluated in healthy volunteers as a single dose after a single high dose of edoxaban, with sustained haemostasis achieved within 10–30 minutes after administration of the candidate antidote.21


The effects in coagulation


induced by this synthetic molecule in individuals with steady-state dosing of edoxaban are currently being assessed.22 Finally, andexanet alfa, an inactive form of Factor Xa, has completed Phase II evaluation in the reversal of anticoagulation with Factor Xa inhibitors,23


and a Phase III trial,


designated ANNEXA-E, specifically with edoxaban, is planned.24


Conclusions


The pharmacological properties of edoxaban provide rapid and specific inhibition of Factor Xa, which is closely related to plasma concentrations. Given the limitations with long-term warfarin therapy, once-daily edoxaban may provide a convenient long-term alternative for patients.7


The results from the Phase III clinical programme for edoxaban constituted a significant therapeutic advance for patients who are intolerant or unsuitable


to treatment with warfarin, leading to regulatory approval of the drug in three major territories. ●


References 1. Daiichi Sankyo. Press release 22 April 2011 . www.daiichisankyo.com/media_investors/ media_relations/press_releases/detail/005806. html.


2. Daiichi Sankyo. Press release 26 September 2014. www.daiichisankyo.com/media_investors/ media_relations/press_releases/detail/006189. html.


3. Daiichi Sankyo. Press release 9 January 2015. www.daiichisankyo.com/media_investors/ media_relations/press_releases/detail/006236. html.


4. Daiichi Sankyo. Press release 25 June 2015. www.daiichisankyo.com/media_investors/ media_relations/press_releases/detail/006314. html.


5. Summary of Product Characteristics. Lixiana. www.medicines.org.uk/emc/medicine/30506.


6. Bounameaux H et al. Edoxaban: An update on the new oral direct factor Xa Inhibitor. Drugs 2014;74:1209–31.


7. Lip GYH et al. Edoxaban: a focused review of its pharmacology. Eur Heart J 2014;35:1844–55.


8. Giugliano RP et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104.


9. Büller HR et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369(15):1406–15.


10. Weitz 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;104:633–41.


11. Aisenberg J et al. Gastrointestinal bleeding with edoxaban versus warfarin: Results from the ENGAGE AF-TIMI 48 Trial. Circulation 2015;132: A17392.


12. Koretsune Y et al. Evaluation of edoxaban in patients with atrial fibrillation and severe renal impairment. Eur Heart J 2013;34 Supp 1.


13. Koretsune Y et al. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment. Circ J 2015;79:1486–95.


14. Parasrampuria DA et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015;113(4):719–27.


15. https://clinicaltrials.gov/ct2/show/NCT02073682 16. https://clinicaltrials.gov/ct2/show/NCT02072434 17. https://clinicaltrials.gov/ct2/show/NCT01802775 ?term=NCT01802775&rank=1


18. Halim AB et al. Ex vivo reversal of the anticoagulant effects of edoxaban. Thromb Res 2014;132(4):909–13.


19. Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: Current status and future potential. Arterioscler Thromb Vasc Biol 2015;35(8):1736–45.


20. Zahir H et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015;131:82–90.


21. Ansell JE et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2140–1.


22. https://clinicaltrials.gov/ct2/show/NCT02207257 ?term=NCT02207257&rank=1


23. https://clinicaltrials.gov/ct2/show/NCT01758432 ?term=NCT01758432&rank=1


24. Portola Pharmaceuticals. http://investors.portola. com/phoenix.zhtml?c=198136&p=irol-newsroom Article&ID=1945318&highlight=


29 www.hospitalpharmacyeurope.com


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