Bruno René, Baille Pascale, Retout Sylvie, Vivier Nicole, Veyrat-Follet Christine, Sanderink Ger-Jan, Becker Richard, Antman Elliott M
Drug Metabolism and Pharmacokinetics, Aventis Pharma, Paris Research Centre, France.
Br J Clin Pharmacol. 2003 Oct;56(4):407-14. doi: 10.1046/j.1365-2125.2003.01904.x.
A major concern with any antithrombotic therapy is an increase in the risk of haemorrhage. The aim of this study was to analyse population pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) relationships for enoxaparin in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI), which may help predict risk of haemorrhage.
Anti-factor Xa (anti-Xa) activity was measured as marker of enoxaparin concentration in 448 patients receiving the drug as a single 30-mg intravenous bolus followed by 1.0 or 1.25 mg kg(-1) subcutaneously twice a day. A population pharmacokinetic analysis was conducted and individual estimates of enoxaparin clearance and area under the curve were tested as prognostic factors for the occurrence of haemorrhagic episodes.
Basic population PK parameters were an enoxaparin clearance of 0.733 l h(-1)[95% confidence interval (CI) 0.698, 0.738], a distribution volume of 5.24 l (95% CI 4.20, 6.28) and an elimination half-life of 5.0 h. Enoxaparin clearance was significantly related to patient weight and creatinine clearance, and was the only independent predictor of experiencing both all (10.7%, P = 0.0013) and major (2.2%, P = 0.0004) haemorrhagic events. A creatinine clearance of 30 ml min(-1) was associated with a decrease in enoxaparin clearance of 27% compared with that in a patient with a median creatinine clearance of 88 ml min-1, and was related to a 1.5- and 3.8-fold increase in the risk of 'all' and 'major' haemorrhagic episodes, respectively.
Enoxaparin clearance depends on body weight, and, therefore, weight-adjusted dosing is recommended to minimize interpatient variability in drug exposure and the risk of haemorrhage. The importance of an increased risk of haemorrhage with decreasing renal function must be weighed against the benefit of treatment with enoxaparin in patients with UA and NSTEMI.
任何抗血栓治疗的一个主要问题是出血风险增加。本研究的目的是分析依诺肝素在不稳定型心绞痛（UA）和非ST段抬高型心肌梗死（NSTEMI）患者中的群体药代动力学及药代动力学/药效学（PK/PD）关系，这可能有助于预测出血风险。
在448例接受药物治疗的患者中，测定抗Xa因子（抗Xa）活性作为依诺肝素浓度的标志物，这些患者先接受一次30mg静脉推注，随后每天两次皮下注射1.0或1.25mg/kg。进行了群体药代动力学分析，并将依诺肝素清除率和曲线下面积的个体估计值作为出血事件发生的预后因素进行检验。
基本群体药代动力学参数为依诺肝素清除率0.733 l/h[95%置信区间（CI）0.698，0.738]，分布容积5.24 l（95%CI 4.20，6.28），消除半衰期5.0 h。依诺肝素清除率与患者体重和肌酐清除率显著相关，并且是发生所有（10.7%，P = 0.0013）和严重（2.2%，P = 0.0004）出血事件的唯一独立预测因素。肌酐清除率为30 ml/min时，与肌酐清除率中位数为88 ml/min的患者相比，依诺肝素清除率降低27%，并且分别与“所有”和“严重”出血事件风险增加1.5倍和3.8倍相关。
依诺肝素清除率取决于体重，因此，建议根据体重调整剂量，以尽量减少患者间药物暴露的变异性和出血风险。在UA和NSTEMI患者中，必须权衡肾功能下降导致出血风险增加的重要性与依诺肝素治疗的益处。
