Population pharmacokinetics and pharmacodynamics of enoxaparin in unstable angina and non‐ST‐segment elevation myocardial infarction

Abstract

Aims 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. Methods 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. Results 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. Conclusions Enoxaparin clearance depends on body weight, and, therefore, weightadjusted 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.

Increased major bleeding risk in patients with kidney dysfunction receiving enoxaparin: a meta-analysis

“…The 24 studies [2-6, 10-11, 14-17, 18-21, 23-25, 27, 29, 31-33] were analyzed word by word. Three studies contained results that were related to the same study population [4,18,27]. The Collet et al study contained several LMWH preparations with 80% of individuals given enoxaparin, but no data could be distinguished for individual preparations or for enoxaparin dosing [10].…”

Enoxaparin dosing in the elderly using adjusted body weight

“…Advantages of LMWH over unfractionated heparin (UFH) include better bioavailability, more predictable and persistent anticoagulant dose response, daily or twice daily subcutaneous (SC) administration, potential for patient self-injection, body weight dosing, and the lack of need for routine laboratory coagulation monitoring [1][2][3]. Serum anti-Xa levels can be used to monitor hemorrhagic risk from enoxaparin, but testing is presently limited to select patient groups such as those with obesity or renal failure [4].…”

Development of an Efficient Sampling Strategy to Predict Enoxaparin Pharmacokinetics in Stage 5 Chronic Kidney Disease

“…[9][10][11] In fact, the apparent clearance of antifactor Xa activity has been reported to be an independent predictor of bleeding complications and hemorrhagic events. 12 This has resulted in recently updated dosing recommendations for enoxaparin in patients with a creatinine clearance less than 30 mL/min. 13 Currently, there is no indication of the appropriate monitoring times for enoxaparin in patients with chronic kidney disease to predict their individualized antifactor Xa exposure.…”