Coadministration of edoxaban with the P-gp inhibitors dronedarone, quinidine, and verapamil increased edoxaban total exposure by 84.5%, 76.7%, and 52.7% respectively compared to edoxaban alone.
RCT (n=220)
Open-label
Randomized
Yes
Does coadministration of cardiovascular P-glycoprotein inhibitors alter the pharmacokinetics of edoxaban in healthy subjects?
Coadministration of edoxaban with P-glycoprotein inhibitors such as quinidine, verapamil, and dronedarone significantly increases edoxaban exposure, highlighting the potential need for dose adjustments in clinical practice.
Effect estimate: Ratio 184.5% (95% CI 177.9-191.4)
Absolute Event Rate: 3070.7% vs 1682.5%
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.
Mendell et al. (Wed,) conducted a rct in Healthy subjects (n=220). Edoxaban coadministered with P-gp inhibitors (dronedarone, quinidine, verapamil, amiodarone, digoxin, atorvastatin) vs. Edoxaban 60 mg alone was evaluated on Edoxaban AUC0-inf (with dronedarone vs alone) (Ratio 184.5%, 95% CI 177.9-191.4). Coadministration of edoxaban with the P-gp inhibitors dronedarone, quinidine, and verapamil increased edoxaban total exposure by 84.5%, 76.7%, and 52.7% respectively compared to edoxaban alone.