Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ, 08837, USA,
Am J Cardiovasc Drugs. 2013 Oct;13(5):331-42. doi: 10.1007/s40256-013-0029-0.
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.
To assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates/inhibitors.
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.
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.
Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin.
依度沙班是一种口服直接因子 Xa 抑制剂，目前正在开发用于血栓预防，包括预防房颤（AF）患者的中风和全身性栓塞。P-糖蛋白（P-gp）是一种外排转运蛋白，调节外源性物质的吸收和排泄。依度沙班是 P-gp 的底物，几种心血管（CV）药物具有抑制 P-gp 和增加药物暴露的潜力。
评估依度沙班与 6 种用于 AF 管理且已知为 P-gp 底物/抑制剂的心血管药物之间潜在的药代动力学相互作用。
在健康受试者中进行了依度沙班与具有已知 P-gp 底物/抑制剂潜力的 CV 药物的药物相互作用研究。在 4 项交叉、2 期、2 治疗研究中，受试者单独接受依度沙班 60mg 治疗，或同时给予奎尼丁 300mg（n=42）、维拉帕米 240mg（n=34）、阿托伐他汀 80mg（n=32）或决奈达隆 400mg（n=34）。此外，在一项单序列研究和两项队列研究中，分别评估了依度沙班 60mg 与胺碘酮 400mg（n=30）或地高辛 0.25mg（n=48）同时给药。
依度沙班的暴露程度（曲线下面积）增加，同时给予依度沙班与奎尼丁（76.7%）、维拉帕米（52.7%）、胺碘酮（39.8%）和决奈达隆（84.5%），同时给予依度沙班与奎尼丁（11.8%）、维拉帕米（29.1%）和决奈达隆（157.6%）的 24 小时浓度也增加。依度沙班与胺碘酮合用使依度沙班的 24 小时浓度降低 25.7%。与地高辛或阿托伐他汀合用对依度沙班的暴露影响很小。
P-gp 抑制剂奎尼丁、维拉帕米和决奈达隆与依度沙班合用可增加依度沙班的暴露。胺碘酮、阿托伐他汀和地高辛的影响较小。
