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, 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.

Figure 1

Population pharmacokinetic model predictions and observed concentrations of enoxaparin (anti-Xa). ——, Population prediction (typical patient); - - - - -, individual predictions (5th, 50th (median), 95th percentiles of 1000 patients). 0 refers to the time of dosing.

Figure 2

Predicted probability of major haemorrhage as a function of enoxaparin clearance.

Figure 3

Predicted incidence of haemorrhage in TIMI-11A population from 100 simulations in 448 patients. CRCL, Creatinine clearance.(a) All haemorrhage. (b) Major haemorrhage.