Uppsala University Hospital, Uppsala, Sweden.
Clin Drug Investig. 2004;24(3):127-36. doi: 10.2165/00044011-200424030-00001.
The oral direct thrombin inhibitor (oral DTI) ximelagatran and its active form, melagatran, which can be administered subcutaneously, were investigated for the prevention and treatment of thromboembolic complications.
In this randomised, double-blind, double-dummy, parallel-group study in patients (n = 90) undergoing general abdominal and/or pelvic surgery, 8-day and 35-day treatment regimens of postoperatively initiated sub-cutaneous (sc) melagatran (3mg twice daily) followed by oral ximelagatran (24mg twice daily) were compared with standard-duration sc dalteparin (5000IU) initiated preoperatively. Pharmacodynamic and pharmacokinetic parameters, efficacy (number of patients with distal and/or proximal deep vein thrombosis [DVT] verified by bilateral venography on the final day of treatment) and safety were assessed.
The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after administration of both sc melagatran and oral ximelagatran. Bioavailability of melagatran was 21% after the first oral dose of ximelagatran and was virtually unchanged throughout the study. Activated partial thromboplastin time increased in a non-linear manner with plasma melagatran concentration. The overall rate of DVT was 11.4% (8/70), with events distributed evenly between treatment groups. Bleeding volumes during surgery tended to be higher in the dalteparin group than in the melagatran/ximelagatran groups. Blood transfusion volumes and numbers of patients transfused were similar in all treatment groups.
Good bioavailability of melagatran was achieved following oral administration of ximelagatran. Postoperative sc melagatran followed by oral ximelagatran appeared to be well tolerated, and the efficacy of standard-length or prolonged prophylaxis with sc melagatran and oral ximelagatran may be comparable to that of dalteparin initiated preoperatively.
口服直接凝血酶抑制剂（口服 DTI）西米拉坦及其活性形式美拉加群，可皮下给药，用于预防和治疗血栓栓塞并发症。
在这项针对接受普通腹部和/或骨盆手术的患者（n=90）的随机、双盲、双模拟、平行组研究中，比较了术后皮下（sc）美拉加群（每日两次，每次 3mg）序贯口服西米拉坦（每日两次，每次 24mg）的 8 天和 35 天治疗方案与术前开始的标准时长 sc 达肝素（5000IU）。评估了药效学和药代动力学参数、疗效（根据治疗结束时的双侧静脉造影术确定的远端和/或近端深静脉血栓形成 [DVT] 患者数量）和安全性。
sc 美拉加群和口服西米拉坦给药后，美拉加群的药代动力学特征可通过一室模型加一级吸收来很好地描述。口服西米拉坦首剂后美拉加群的生物利用度为 21%，在整个研究过程中基本保持不变。部分凝血活酶时间随血浆美拉加群浓度呈非线性增加。DVT 的总发生率为 11.4%（8/70），各组事件分布均匀。与达肝素组相比，美拉加群/西米拉坦组术中出血体积有增高趋势。输血体积和输血患者数量在所有治疗组中相似。
口服西米拉坦后美拉加群具有良好的生物利用度。术后皮下美拉加群序贯口服西米拉坦耐受性良好，标准长度或延长 sc 美拉加群和口服西米拉坦的预防效果可能与术前开始的达肝素相当。
