Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Abstract

Background-The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low-molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low-molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem. Method and Results-Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance.Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling. One hundred twentythree patients contributed 795 anti-Xa activities for pharmacokinetic modeling 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 regimens 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-The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered. Patel et al Population PK of Enoxaparin During Pregnancy 1463of Obstetricians and Gynaecologists (RCOG) guidelines for the management of antenatal VTE suggest a twice-daily dose of enoxaparin or dalteparin, 9 whereas the American College of Chest Physicians guidelines state that a once-or twice-daily dose could be used, acknowledging the uncertainty that exists around the optimal LMWH dosing regimen for this indication. 10 The evidence for increasing the total daily dose or dosing frequency during pregnancy is based on small, historical, observational studies.11-27 Prescribing a twice-daily dosing regimen of LMWH has significant implications for women with respect to injection burden, particularly if the VTE event occurs early during pregnancy. Clinical Perspective on p 1469We developed a population pharmacokinetic model 28 to better understand the specific pharmacokinetic changes in LMWH during pregnancy and, through pharmacokinetic simulation, determined the optimal dosing strategy to use during pregnancy for the treatment of antenatal VTE. MethodsPregnant women ≥18 years of age who were referred to the specialist thrombophilia clinic at King's College Hospital were eligible for recruitment to the study. King's Co...

Re: Pregnancy outcomes in women with mechanical prosthetic heart valves – a prospective descriptive population‐based study using the United Kingdom Obstetric Surveillance System (UKOSS) data collection system

“…Sir, We thank Patel et al 1 for their interest in our paper 2 and agree with their comments about the physiological changes in pregnancy and the importance of trough Anti Xa levels.…”

“…2 This demonstrates that as pregnancy progresses, if a woman is given the same dose of LMWH throughout pregnancy, a gradual increase in the trough concentration is observed during pregnancy, illustrating the prolongation of the half-life of enoxaparin. Others have reported similar findings.…”

Venous thromboembolism in obese pregnant women: approach to diagnosis and management

“…Pregnancy-related physiologic adaptation resulting in amplification of maternal blood volume peaking in the third trimester at around 50%, augmentation of glomerular filtration with higher renal excretion, and enhancement of protein-binding, alter the pharmacokinetic properties of LMWH and UFH [55]. Twice-daily dosing for maintenance of therapeutic levels has been proposed by some [16,31], while once-daily dosing is supported by others [55]. Similarly, the need for anti-FXa monitoring remains unclear [9,16,31].…”

Treatment of pregnancy-associated venous thromboembolism - position paper from the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH)

“…However, the data on this topic are confl icting [21,23]. Two studies investigating the pharmacological profi le of enoxaparin in pregnancy revealed a decrease in peak aXa levels at 3 hours after subcutaneous injection and an increase in trough aXa activities, which the authors attributed to an increase in plasma volume and the apparent volume of distribution [24,25]. The authors concluded that the consecutive prolongation of enoxaparin elimination half-life that was observed during the progress of pregnancy favoured a once-daily dose regimen in pregnant patients and that determining dose adjustments based on peak aXa levels may not be appropriate during pregnancy.…”