Optimal dosing of enoxaparin in overweight and obese children

Abstract

Aim Current enoxaparin dosing guidelines in children are based on total body weight. This is potentially inappropriate in obese children as it may overestimate the drug clearance. Current evidence suggests that obese children may require lower initial doses of enoxaparin, therefore the aim of this work was to characterise the pharmacokinetics of enoxaparin in obese children and to propose a more appropriate dosing regimen. Methods Data from 196 unique encounters of 160 children who received enoxaparin treatment doses were analysed. Enoxaparin concentration was quantified using the chromogenic anti factor Xa (anti‐Xa) assay. Patients provided a total of 552 anti‐Xa samples. Existing published pharmacokinetic (PK) models were fitted and evaluated against our dataset using prediction‐corrected visual predictive check plots (pcVPCs). A PK model was fitted using a nonlinear mixed‐effects modelling approach. The fitted model was used to evaluate the current standard dosing and identify an optimal dosing regimen for obese children. Results Published models of enoxaparin pharmacokinetics in children did not capture the pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one‐compartment model with linear elimination best described the pharmacokinetics of enoxaparin. Allometrically scaled fat‐free mass with an estimated exponent of 0.712 (CI 0.66‐0.76) was the most influential covariate on clearance while linear fat‐free mass was selected as the covariate on volume. Simulations from the model showed that fat‐free mass‐based dosing could achieve the target anti‐Xa activity at steady state in 77.5% and 78.2% of obese and normal‐weight children, respectively, compared to 65.2% and 75.5% for standard total body weight‐based dosing. Conclusions A population PK model that describes the time course of anti‐Xa activity of enoxaparin was developed in a paediatric population. Based on this model, a unified dosing regimen was proposed that will potentially improve the success rate of target attainment in overweight/obese patients without the need for patient body size categorisation. Therefore, prospective validation of the proposed approach is warranted.

Enoxaparin treatment dosing for venous thromboembolism in pediatric patients with obesity

“…13 Recent pediatric pharmacokinetic analyses have demonstrated that enoxaparin dosing based on fat-free mass or allometrically scaled weight predicts its exposure better than total bodyweight-based dosing. [14][15][16] Despite its potential for better therapeutic level attainment, alternative dosing strategies warrant further validation. Until then, it is imperative to have a better understanding of the relationship between enoxaparin dosing requirements and total bodyweight in pediatric obesity.…”

“…However, metabolic processes such as drug clearance mostly occur within lean tissues, and using total bodyweight to calculate enoxaparin dose for obese patients has raised a concern for over‐anticoagulation 13 . Recent pediatric pharmacokinetic analyses have demonstrated that enoxaparin dosing based on fat‐free mass or allometrically scaled weight predicts its exposure better than total bodyweight‐based dosing 14–16 . Despite its potential for better therapeutic level attainment, alternative dosing strategies warrant further validation.…”

Paediatric medicine issues and gaps from healthcare workers point of view: survey results and a narrative review from the global accelerator for paediatric formulations project

“…Indeed, dosing adaptation is needed, especially for overweight or obese children ( Derbalah et al, 2022 ) as well as for infants and young children who require higher enoxaparin doses than adults to achieve therapeutic anti-factor Xa levels ( Wysocki et al, 2021 ).…”

Perioperative Acetaminophen Dosing in Obese Children

“…It is lacking for obese children, but has potential use in the investigation of pharmacokinetics in these children. Enoxyparin dose, for example, has been investigated in obese children using both PBPK [ 39 ] and compartment models [ 40 ]; both methods concluded that fat-free mass was a good size scaler to use for Enoxyparin dose estimation in obese children.…”