Population pharmacokinetics of enoxaparin during the antenatal period.
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.


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 twenty-three 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.
King's Thrombosis Centre, Department of Haematological Medicine (J.P.P., R.K.P., R.A.), and Department of Obstetrics and Gynaecology (M.S.M.), King's College Hospital NHS Foundation Trust, UK; Institute of Pharmaceutical Science, King's College London, UK (J.P.P., J.G.D.); and Model Answers Pty Ltd, Australia (B.G.).
Jignesh P
JP
Patel
Bruce
B
Green
Raj K
RK
Patel
Michael S
MS
Marsh
J Graham
JG
Davies
Roopen
R
Arya
D000925:Anticoagulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D011247:Pregnancy / Q000097:blood* / Q000187:drug effects; D011295:Prenatal Care / Q000379:methods*; D054556:Venous Thromboembolism / Q000097:blood / Q000517:prevention & control
D000925:Anticoagulants; D017984:Enoxaparin
enoxaparin; heparin, low-molecular-weight; pharmacokinetics; pregnancy; venous thromboembolism