Institute for Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany.
Thromb Haemost. 2010 Mar;103(3):572-85. doi: 10.1160/TH09-09-0659. Epub 2010 Feb 2.
Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the factor Xa inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and apixaban throughout preclinical and clinical development.
治疗性口服抗凝通常通过给予华法林或其他维生素 K 拮抗剂来实现，这些药物与不良的药代动力学/药效学（PK/PD）特征相关，导致出血并发症或治疗失败的发生率较高。因此，存在对新型易于使用的口服抗凝剂的未满足的医疗需求，这些抗凝剂具有改善的疗效和安全性。最近的发展包括鉴定选择性抑制凝血级联中某些丝氨酸蛋白酶的非肽小分子。其中，凝血酶抑制剂达比加群和因子 Xa 抑制剂利伐沙班最近已在欧洲获得骨科手术后血栓预防的许可。此外，因子 Xa 抑制剂阿哌沙班处于临床开发后期。每种药物均以固定剂量开处方，无需进行抗凝监测。骨科患者的 III 期试验基本上表明达比加群的疗效非劣效于依诺肝素，利伐沙班的疗效优于依诺肝素，且药物安全性无明显差异，而阿哌沙班的数据仍存在争议。然而，CYP3A4 或 P-糖蛋白的抑制剂和诱导剂与利伐沙班和阿哌沙班的药代动力学相互作用可能会使这些化合物在日常实践中的使用复杂化，而达比加群的消除主要取决于肾功能。因此，本综述报告了达比加群、利伐沙班和阿哌沙班在临床前和临床开发过程中的 PK/PD、疗效和安全性数据。
