South Dakota State University, Sioux Falls, SD, USA.
Ann Pharmacother. 2013 Nov;47(11):1478-87. doi: 10.1177/1060028013504741. Epub 2013 Oct 9.
To review pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs) involving new oral anticoagulants for atrial fibrillation.
A literature search was conducted via PubMed and the Cochrane database to identify DDI studies using the terms drug interactions, dabigatran, rivaroxaban, and apixaban. Prescribing information and Food and Drug Administration briefing documents were used to supplement published data.
English publications identified on Medline from 2005 up to August 2013 and US prescribing information for approved oral anticoagulants.
Articles reviewed focused on drugs affecting the permeability glycoprotein (P-gp) efflux transporter protein and/or cytochrome P (CYP) 450 3A4 enzymes, and pharmacodynamic DDIs when drugs are administered concomitantly. Phase I DDI studies have reported pharmacokinetic DDIs mediated by P-gp alone (dabigatran etexilate) or in combination with CYP3A4 enzymes (rivaroxaban and apixaban). Dabigatran etexilate should not be administered with any P-gp inhibitor in patients with severe renal impairment. Briefing documents indicate that rivaroxaban and apixaban should not be used with drugs that are strong inhibitors of both P-gp and CYP3A4. DDI studies involving rifampicin suggest that rivaroxaban and apixaban should be avoided when strong inducers of P-gp and CYP3A4 are used concurrently. Concomitant use of apixaban and strong dual inhibitors of P-gp and CYP3A4 should be avoided or the dose reduced. Five randomized clinical trials report additive effects with rivaroxaban, dabigatran, and apixaban when used concomitantly with antiplatelet agents; bleeding rates have been found to be higher, especially with dual antiplatelet therapy.
Awareness of drugs that alter the function of the P-gp efflux transporter protein and CYP3A4 enzymes and provide additive effects should enable prescribers to anticipate and avoid potential DDIs involving the new oral anticoagulants. To this end, briefing documents and prescribing information have applied cautionary measures for individuals treated with these newer anticoagulants.
综述新的口服抗凝剂用于房颤的药物代谢动力学和药效学药物相互作用（DDI）。
通过 PubMed 和 Cochrane 数据库检索药物相互作用、达比加群、利伐沙班和阿哌沙班等术语的 DDI 研究。使用处方信息和美国食品和药物管理局简报文件补充已发表的数据。
从 2005 年到 2013 年 8 月，在 Medline 上检索英文出版物，并查阅已批准的口服抗凝剂的美国处方信息。
综述的文章主要关注影响通透性糖蛋白（P-gp）外排转运蛋白和/或细胞色素 P（CYP）450 3A4 酶的药物，以及同时给予药物时的药效学 DDI。I 期 DDI 研究报告了由 P-gp 单独（达比加群酯）或与 CYP3A4 酶联合介导的药代动力学 DDI。在严重肾功能不全的患者中，不应给予达比加群酯与任何 P-gp 抑制剂。简报文件表明，利伐沙班和阿哌沙班不应与既是 P-gp 又是 CYP3A4 的强抑制剂的药物一起使用。涉及利福平的 DDI 研究表明，当同时使用 P-gp 和 CYP3A4 的强诱导剂时，应避免使用利伐沙班和阿哌沙班。同时使用阿哌沙班和 P-gp 和 CYP3A4 的双重强抑制剂应避免或减少剂量。五项随机临床试验报告了利伐沙班、达比加群和阿哌沙班与抗血小板药物同时使用时的相加作用；已发现出血率更高，尤其是在双重抗血小板治疗时。
了解改变 P-gp 外排转运蛋白和 CYP3A4 酶功能并产生相加作用的药物，应使处方者能够预测并避免涉及新型口服抗凝剂的潜在 DDI。为此，简报文件和处方信息为使用这些新型抗凝剂的个体采取了谨慎措施。
