Cardiology Xagena

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Oral factor Xa inhibitors: coadministration of the P-gp inhibitors Quinidine, Verapamil, and Dronedarone increases Edoxaban exposure

Edoxaban ( Lixiana ), an oral direct factor Xa inhibitor, is in development for thromboprophylaxis, including prevention of stroke and systemic embolism in patients with atrial fibrillation.
P-glycoprotein ( P-gp ), an efflux transporter, modulates absorption and excretion of xenobiotics. Edoxaban is a P-gp substrate, and several cardiovascular drugs have the potential to inhibit P-gp and increase drug exposure.

The purpose of a study was to assess the potential pharmacokinetic interactions of Edoxaban and 6 cardiovascular drugs used in the management of atrial fibrillation and known P-gp substrates / inhibitors.

Drug-drug interaction studies with Edoxaban and cardiovascular drugs with known P-gp substrate / inhibitor potential were conducted in healthy subjects.
In 4 crossover, 2-period, 2-treatment studies, subjects received Edoxaban 60 mg alone and coadministered with Quinidine 300 mg ( n = 42 ), Verapamil 240 mg ( n = 34 ), Atorvastatin 80 mg ( n = 32 ), or Dronedarone 400 mg ( n = 34 ).

Additionally, Edoxaban 60 mg alone and coadministered with Amiodarone 400 mg ( n = 30 ) or Digoxin 0.25 mg ( n = 48 ) was evaluated in a single-sequence study and 2-cohort study, respectively.

Edoxaban exposure measured as area under the curve increased for concomitant administration of Edoxaban with Quinidine ( 76.7% ), Verapamil ( 52.7% ), Amiodarone ( 39.8% ), and Dronedarone ( 84.5% ), and exposure measured as 24-h concentrations for Quinidine ( 11.8% ), Verapamil ( 29.1% ), and Dronedarone ( 157.6% ) also increased.

Administration of Edoxaban with Amiodarone decreased the 24-h concentration for edoxaban by 25.7%.

Concomitant administration with Digoxin or Atorvastatin had minimal effects on Edoxaban exposure.

In conclusion, the coadministration of the P-gp inhibitors Quinidine, Verapamil, and Dronedarone increased Edoxaban exposure.
Modest / minimal effects were observed for Amiodarone, Atorvastatin, and Digoxin. ( Xagena )

Mendell J et al, Am J Cardiovasc Drugs 2013;13:331-342