Abstract 1071

Poster Board I-93

Introduction:

Enoxaparin, a low-molecular-weight-heparin (LMWH), is used off-label in children to prevent symptomatic thromboembolism when acute anticoagulation or secondary prevention is required due to venous thrombosis or stroke. This investigation was conducted because of concerns of altered pharmacokinetics and a lack of safety and efficacy data when used in children.

Patients and Methods:

Data of 126 children and adolescents with a median age of 5.9 years receiving enoxaparin either as a once or twice daily dosing regimen were analyzed. Children < 12 months of age received a starting dose of 1.5 mg/kg followed by a maintenance dose of 1.3 mg/kg. Children > 12 months of age were started on 1 mg/kg followed by a maintenance dose of 1 mg/kg. Blood samples were drawn after patients reached steady-state on their maintenance dose at baseline prior to the next dose, and at 2, 4, 8 and 12 hours after administration. The median enoxaparin concentration in our population resulted in a median anti-factor Xa activity of 0.4 U/ml (range 0 – 1 U/ml anti-factor Xa). By means of population pharmacokinetics using nonlinear mixed-effects modelling (NONMEM) plasma concentration-time data were analyzed. Several covariates such as age, body weight and body surface area were tested on their effects on the pharmacokinetic parameters.

Results:

Using a two-compartment model the enoxaparin kinetics were described sufficiently. By using body weight and age as covariates for clearance (CL) and central volume of distribution (V1) the best results were obtained. The final population estimates of enoxaparin resulted to be: CL 7.11 ml h-1 kg-1 ± 14.3%, V1 7.31 ml kg-1 ± 33.5%, intercompartimental clearance (Q) 194 ml h-1 ± 24.7%, peripheral volume of distribution (V2) 45.1 l ± 52.5% and absorption rate (ka) 0.0799 h-1 ± 21.7% (estimates ± standard errors). Interindividual variability (IIV) was found to be 75.6% for CL and 78.4% for Q, respectively. Figure 1 shows the predicted activity time-course versus the measured activities for a representative patient. The model is capable of describing all aging and dosing groups of our childhood population (neonates, infants to adolescents).

Conclusion:

The high IIV in CL and Q in our population underlines the need for monitoring the activity and individualizing the dose. Further population pharmacokinetic/-dynamic investigations should be conducted to predict target enoxaparin levels or other new antithrombotic drugs for more safety and efficacy during antithrombotic therapy when used in children.

Figure 1:
Figure 1:. Model predicted anti-factor Xa activity for one selected patient (dashed line = individual predicted plasma concentration, solid line = population model predicted plasma concentration, dots = measured plasma concentrations)
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Model predicted anti-factor Xa activity for one selected patient (dashed line = individual predicted plasma concentration, solid line = population model predicted plasma concentration, dots = measured plasma concentrations)

Figure 1:
Figure 1:. Model predicted anti-factor Xa activity for one selected patient (dashed line = individual predicted plasma concentration, solid line = population model predicted plasma concentration, dots = measured plasma concentrations)
View largeDownload slide

Model predicted anti-factor Xa activity for one selected patient (dashed line = individual predicted plasma concentration, solid line = population model predicted plasma concentration, dots = measured plasma concentrations)

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Disclosures:

Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism..

Topics:
enoxaparin, pharmacokinetics, thromboembolism, child at risk, anti factor xa, drug maintenance dose, low-molecular-weight heparin, off-label use, fibrinolytic agents, anticoagulation

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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