Gustafsson D
AstraZeneca R&D, Mölndal, Sweden.
J Intern Med. 2003 Oct;254(4):322-34. doi: 10.1046/j.1365-2796.2003.01225.x.
Thrombin has long been a target for development of oral anticoagulants but it has been difficult to find synthetic inhibitors with a desirable combination of pharmacodynamic and pharmacokinetic properties. However, there are now two oral direct thrombin inhibitors (DTIs) in clinical development, ximelagatran (ExantaTM) and BIBR 1048. Both are prodrugs with two protecting groups that are eliminated after absorption from the gastrointestinal tract. Their main active substances, melagatran and BIBR 953, are both potent and selective DTIs. In experimental models of thrombosis, melagatran has been shown to have a shallower dose-response curve than warfarin and, therefore, a better separation between efficacy and bleeding. Oral bioavailability, measured as the plasma concentration of the active metabolite, seems to be higher for ximelagatran (20%) than for BIBR 1048 (estimated to 5%). BIBR 953 has a longer half-life (about 12 h) than does melagatran (3-5 h) after oral administration of BIBR 1048 and ximelagatran, respectively. Both melagatran and BIBR 953 are mainly eliminated via the renal route. The variability of the plasma concentration of melagatran after oral administration of ximelagatran is low. There are no clinically relevant interactions with food or cytochrome P450 metabolized drugs and ximelagatran. In clinical studies, ximelagatran has been administered in a twice-daily fixed-dose regimen without coagulation monitoring. Results of published clinical studies are encouraging, both with regard to efficacy and bleeding. Major indications in Phase III studies with ximelagatran are the prevention of venous thromboembolism (VTE) in hip and knee replacement surgery, treatment and long-term secondary prevention of VTE and prevention of stroke in patients with nonvalvular atrial fibrillation. It is anticipated that with a favourable outcome of the Phase III clinical studies new oral DTIs, with the oral fixed-dose regimen without routine coagulation monitoring, will ease the use of today's anticoagulant therapy.
长期以来，凝血酶一直是口服抗凝剂研发的靶点，但很难找到具有理想的药效学和药代动力学特性组合的合成抑制剂。然而，目前有两种口服直接凝血酶抑制剂（DTIs）正在进行临床开发，即希美加群（ExantaTM）和BIBR 1048。两者都是前体药物，带有两个保护基团，在从胃肠道吸收后被消除。它们的主要活性物质，美拉加群和BIBR 953，都是强效且选择性的DTIs。在血栓形成的实验模型中，已表明美拉加群的剂量 - 反应曲线比华法林更平缓，因此，在疗效和出血之间有更好的区分。以活性代谢物的血浆浓度衡量的口服生物利用度，希美加群（20%）似乎比BIBR 1048（估计为5%）更高。分别口服BIBR 1048和希美加群后，BIBR 953的半衰期（约12小时）比美拉加群（3 - 5小时）更长。美拉加群和BIBR 953都主要通过肾脏途径消除。口服希美加群后美拉加群血浆浓度的变异性较低。与食物或细胞色素P450代谢的药物以及希美加群没有临床相关的相互作用。在临床研究中，希美加群采用每日两次的固定剂量方案给药，无需进行凝血监测。已发表的临床研究结果在疗效和出血方面都令人鼓舞。希美加群III期研究的主要适应症是在髋关节和膝关节置换手术中预防静脉血栓栓塞（VTE）、VTE的治疗和长期二级预防以及非瓣膜性心房颤动患者的中风预防。预计随着III期临床研究取得良好结果，新型口服DTIs以及无需常规凝血监测的口服固定剂量方案将使当今的抗凝治疗使用更加简便。
