Optimal Dosing of Enoxaparin in Overweight and Obese Children

Aim:Current enoxaparin dosing guidelines in children are based on total bodyweight. This is potentially inappropriate in obese children as it may overestimate thedrug clearance. Current evidence suggests that obese children may require lower ini-tial doses of enoxaparin, therefore the aim of this work was to characterise the phar-macokinetics of enoxaparin in obese children and to propose a more appropriatedosing regimen.Methods:Data from 196 unique encounters of 160 children who received enoxa-parin treatment doses were analysed. Enoxaparin concentration was quantified usingthe chromogenic anti factor Xa (anti-Xa) assay. Patients provided a total of 552 anti-Xa samples. Existing published pharmacokinetic (PK) models were fitted and evalu-ated 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 anoptimal dosing regimen for obese children.Results:Published models of enoxaparin pharmacokinetics in children did not capturethe pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one-compartment model with linear elimination best described the pharmacokinetics ofenoxaparin. 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-freemass was selected as the covariate on volume. Simulations from the model showedthat fat-free mass-based dosing could achieve the target anti-Xa activity at steadystate in 77.5% and 78.2% of obese and normal-weight children, respectively, com-pared 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 activ-ity of enoxaparin was developed in a paediatric population. Based on this model, aunified dosing regimen was proposed that will potentially improve the success rate oftarget attainment in overweight/obese patients without the need for patient bodysize categorisation. Therefore, prospective validation of the proposed approach iswarranted

Optimal Dosing of Enoxaparin in Overweight and Obese Children

Aim:Current enoxaparin dosing guidelines in children are based on total bodyweight. This is potentially inappropriate in obese children as it may overestimate thedrug clearance. Current evidence suggests that obese children may require lower ini-tial doses of enoxaparin, therefore the aim of this work was to characterise the phar-macokinetics of enoxaparin in obese children and to propose a more appropriatedosing regimen.Methods:Data from 196 unique encounters of 160 children who received enoxa-parin treatment doses were analysed. Enoxaparin concentration was quantified usingthe chromogenic anti factor Xa (anti-Xa) assay. Patients provided a total of 552 anti-Xa samples. Existing published pharmacokinetic (PK) models were fitted and evalu-ated 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 anoptimal dosing regimen for obese children.Results:Published models of enoxaparin pharmacokinetics in children did not capturethe pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one-compartment model with linear elimination best described the pharmacokinetics ofenoxaparin. 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-freemass was selected as the covariate on volume. Simulations from the model showedthat fat-free mass-based dosing could achieve the target anti-Xa activity at steadystate in 77.5% and 78.2% of obese and normal-weight children, respectively, com-pared 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 activ-ity of enoxaparin was developed in a paediatric population. Based on this model, aunified dosing regimen was proposed that will potentially improve the success rate oftarget attainment in overweight/obese patients without the need for patient bodysize categorisation. Therefore, prospective validation of the proposed approach iswarranted

Optimal Dosing of Enoxaparin in Overweight and Obese Children

Aim:Current enoxaparin dosing guidelines in children are based on total bodyweight. This is potentially inappropriate in obese children as it may overestimate thedrug clearance. Current evidence suggests that obese children may require lower ini-tial doses of enoxaparin, therefore the aim of this work was to characterise the phar-macokinetics of enoxaparin in obese children and to propose a more appropriatedosing regimen.Methods:Data from 196 unique encounters of 160 children who received enoxa-parin treatment doses were analysed. Enoxaparin concentration was quantified usingthe chromogenic anti factor Xa (anti-Xa) assay. Patients provided a total of 552 anti-Xa samples. Existing published pharmacokinetic (PK) models were fitted and evalu-ated 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 anoptimal dosing regimen for obese children.Results:Published models of enoxaparin pharmacokinetics in children did not capturethe pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one-compartment model with linear elimination best described the pharmacokinetics ofenoxaparin. 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-freemass was selected as the covariate on volume. Simulations from the model showedthat fat-free mass-based dosing could achieve the target anti-Xa activity at steadystate in 77.5% and 78.2% of obese and normal-weight children, respectively, com-pared 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 activ-ity of enoxaparin was developed in a paediatric population. Based on this model, aunified dosing regimen was proposed that will potentially improve the success rate oftarget attainment in overweight/obese patients without the need for patient bodysize categorisation. Therefore, prospective validation of the proposed approach iswarranted