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Randomized Controlled Trial
. 2013 Oct;13(5):331-42.
doi: 10.1007/s40256-013-0029-0.

Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor

Jeanne Mendell  1 , Hamim Zahir, Nobuko Matsushima, Robert Noveck, Frank Lee, Shuquan Chen, George Zhang, Minggao Shi
Affiliations
Randomized Controlled Trial

Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor

Jeanne Mendell et al. Am J Cardiovasc Drugs. 2013 Oct.

Abstract

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

Objective: To assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates/inhibitors.

Methods: Drug-drug interaction studies with edoxaban and CV 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.

Results: 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.

Conclusion: Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin.

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Figures

Fig. 1
Fig. 1
Ratios of Cmax and AUC for edoxaban with and without interacting drug. Geometric least squares means. AUC0–inf for amiodarone, atorvastatin, and dronedarone; AUC0–24 for quinidine and verapamil; AUC0–τ for digoxin. Reference indicates edoxaban
Fig. 2
Fig. 2
Ratios of C24 (plasma concentration at 24 h postdose) for edoxaban with and without interacting drug. Arithmetic means. Test indicates edoxaban plus interacting drug; reference, edoxaban
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