Population Pharmacokinetics of Enoxaparin during the Antenatal Period
Background—The optimal dosing strategy of low molecular weight heparins (LMWH) for the treatment of antenatal venous thromboembolism (VTE) is not known. The physiological changes associated with pregnancy alter the pharmacokinetic (PK) profile of LMWH, which has led to controversy and subsequent variation in practice, when pregnant women with VTE are treated with LMWH. Our objective was to develop a robust PK model of enoxaparin during the antenatal period to address this problem.
Methods and Results—Women prescribed antenatal enoxaparin, were eligible to enrol in the study. Recruited women were reviewed monthly, and had up to three anti-Xa activities (trough, 1 hour post dose, and 3 hours post dose) drawn at each clinic attendance. Compartmental PK modelling was conducted using non linear mixed effects modelling. One hundred and twenty three patients contributed 795 anti-Xa activities for PK modelling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once versus twice daily enoxaparin administration demonstrated that both dosing regimens would reach target 3 hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once and twice daily regimes exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy.
Conclusions—Enoxaparin's half-life is prolonged with the progression of pregnancy and our work provides compelling evidence for prescribing once daily enoxaparin for the treatment of antenatal VTE. National and international guideline recommendations should be re-considered.
- Received April 12, 2013.
- Revision received July 4, 2013.
- Accepted August 5, 2013.