Dr. Yu Chen Barrett, Bristol-Myers Squibb, 777 Scudders Mill Road, Plainsboro, NJ 08536-1695, USA.
Thromb Haemost. 2012 May;107(5):916-24. doi: 10.1160/TH11-09-0634. Epub 2012 Mar 8.
Following major orthopaedic surgery, guidelines usually recommend continued thromboprophylaxis after hospitalisation. The availability of an effective oral anticoagulant with an acceptable safety profile that does not require routine clinical monitoring may lead clinicians to switch patients from subcutaneous to an oral therapy either during hospitalisation or at discharge. The purpose of this study was to assess the effect of enoxaparin on the pharmacokinetics, pharmacodynamics and safety of apixaban, an oral, direct inhibitor of coagulation factor Xa. In this four-period, crossover study, 20 healthy subjects were randomised to receive single doses of apixaban 5 mg orally; enoxaparin 40 mg subcutaneously; apixaban 5 mg and enoxaparin 40 mg concomitantly; and apixaban 5 mg followed 6 hours (h) after by enoxaparin 40 mg. Pharmacokinetics of apixaban were not affected by enoxaparin. Average peak pharmacodynamic effect, measured by anti-Xa activity, was 1.36 U/ml after administration of apixaban and was 0.42 U/ml after enoxaparin. Following co-administration of apixaban and enoxaparin, peak anti-Xa activity was 42% higher than for apixaban alone. Following administration of enoxaparin 6 h after apixaban, peak anti-Xa activity was 15% higher than for apixaban alone. In conclusion, enoxaparin had no effect on the pharmacokinetics of apixaban. The increase in anti-Xa activity after co-administration was modest and appeared to be additive. Peak anti-Xa activity increases are mitigated by separating administration of subcutaneous anticoagulation and apixaban when switching between therapies; the potential for pharmacodynamic interaction may be further mitigated by transitioning at the next scheduled dose (12 h).
在接受重大骨科手术后，指南通常建议在住院后继续进行血栓预防。如果有一种有效的口服抗凝剂，其具有可接受的安全性，且不需要常规临床监测，那么临床医生可能会在住院期间或出院时将患者从皮下治疗转换为口服治疗。本研究的目的是评估依诺肝素对口服、直接凝血因子 Xa 抑制剂阿哌沙班的药代动力学、药效学和安全性的影响。在这项四周期交叉研究中，20 名健康受试者被随机分配接受单次口服阿哌沙班 5mg；皮下依诺肝素 40mg；阿哌沙班 5mg 和依诺肝素 40mg 同时给药；以及阿哌沙班 5mg 给药 6 小时（h）后给予依诺肝素 40mg。依诺肝素不影响阿哌沙班的药代动力学。抗-Xa 活性测定的平均峰值药效学效应为阿哌沙班给药后 1.36U/ml，依诺肝素给药后为 0.42U/ml。阿哌沙班和依诺肝素同时给药后，峰值抗-Xa 活性比单独使用阿哌沙班高 42%。阿哌沙班给药后 6 小时给予依诺肝素时，峰值抗-Xa 活性比单独使用阿哌沙班高 15%。总之，依诺肝素对阿哌沙班的药代动力学没有影响。联合用药后抗-Xa 活性的增加是适度的，似乎是相加的。当在治疗方案之间转换时，通过将皮下抗凝药物和阿哌沙班的给药时间分开，可以减轻峰值抗-Xa 活性的增加；通过在下次预定剂量（12 小时）转换，可能进一步减轻药效学相互作用的潜力。
