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Optimal dosing of enoxaparin in overweight and obese children

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.


| INTRODUCTION
Enoxaparin is a commonly used anticoagulant for treating and preventing thromboembolic disorders in children. Common indications for enoxaparin include deep venous thrombosis/pulmonary embolism, coronary heart disease and prophylaxis in cases of increased thrombotic risk such as surgery and infections. Enoxaparin has largely replaced unfractionated heparin as the parenteral anticoagulant of choice for the management of thrombosis due to favourable pharmacokinetic properties such as a longer half-life and higher subcutaneous bioavailability. It has been shown to achieve similar effectiveness without an increase in the incidence of major bleeding events. 1 This has been purported to be due to a more predictable dose-response relationship. 2 Dosing guidelines of enoxaparin for paediatric patients typically suggest an initial treatment dose of 1 mg/kg (of total body weight) twice daily, targeting a peak (4 hours post-dose) anti-Xa (aXa) activity of 0.5-1 IU/mL. 3,4 A recent population analysis showed that this dose has a 72.3% probability of achieving the aXa concentration target in hospitalised paediatric patients. 5 Maintenance dosing based on total body weight (Wt) implies that enoxaparin clearance is linearly proportional to Wt. However, this has often been found to be inaccurate in overweight/obese individuals. 6,7 As the body's metabolic processes occur primarily in lean tissues, overweight/obese individuals tend to have lower drug clearance per kilogram of Wt. Therefore, dosing based on Wt will potentially result in overdosing in this population. It has been reported that overweight/obese children achieve a significantly higher aXa activity compared to nonobese children when dosed on a Wt basis. 8 A recent review has shown that overweight/obese paediatric patients required a 12.9% to 37.3% average dose reduction, suggesting they may require lower initial enoxaparin Wt-based doses. 9 Data on the clinical outcomes of enoxaparin treatment in overweight/obese children versus normal-weight children are lacking.
However, elevated aXa levels are associated with a higher risk of adverse effects such as bleeding.
The issue of dosing obese patients is becoming more critical as the prevalence of obesity is increasing worldwide. 10 Obesity in adults is usually defined based on the absolute value of body mass index (BMI). 10 However, children are classified as overweight if their BMI is greater than the 85th but less than the 95th percentile respective to age and sex, whereas obesity is defined as a BMI exceeding the 95th percentile for age and sex. 11 In adults, the risk of overdosing obese patients is minimised through alternative practices. A popular alternative to dosing in the obese is to reduce the dose to 0.75 mg/kg twice daily. 12 However, this approach has only been assessed in morbidly obese patients. An alternative dosing strategy is based on fat-free mass (FFM), which has been shown to result in fewer bleeding/ bruising events without a decrease in drug effectiveness. 13,14 Some practices also implement dose capping at 100 mg per dose. 15 No alternative dosing strategies have been used or explored in the paediatric population.

| Objectives
The objectives of this study were (1) to evaluate the performance of published models of enoxaparin pharmacokinetics against our dataset in both normal-weight and overweight/obese children, (2) to develop and evaluate a population pharmacokinetic (PK) model to predict the optimal dosing regimen of enoxaparin in overweight/obese paediatric patients and (3) to evaluate the current dosing guidelines in overweight/obese children and identify optimal dosing strategies for those patients.

| Data
The data used in this analysis consisted of retrospectively collected aXa measurements from 160 paediatric patients who received a What is already known about this subject • Enoxaparin is typically dosed in children on a milligrams per kilogram basis, which may be suboptimal when used in obese children.
• With standard dosing, obese children achieve higher anti-Xa activity and require more frequent dose reduction compared to normal-weight children.
• No alternative dosing regimens for enoxaparin have been proposed/explored in obese children.

What this study adds
• The first population model was developed for enoxaparin pharmacokinetics in obese children.
• The model was used to identify a dosing regimen of enoxaparin that consistently achieves the target anti-Xa activity in both obese and normal-weight children.
• The proposed regimen potentially eliminates the need for categorising children based on their body weight and simplifies dose calculation in clinical practice. treatment dose of enoxaparin between 1 January 1996 and 31 December 2016 in the Primary Children's Hospital, Salt Lake City, Utah, USA, and had at least one recorded aXa measurement. The study received approval from the University of Utah institutional review board (IRB# 01101489). All patients who concomitantly received other anticoagulants were excluded from the study. As per institutional protocol, infants younger than 2 months received 1.5 mg/kg every 12 hours while older infants and children received 1 mg/kg every 12 hours. aXa activity was determined using the chromogenic one-stage assay (Heparin anti-Xa LMWH 0030144 kit; Diagnotsica Stago, Milan, Italy) with a lower limit of quantification of 0.1 IU/mL. The intra-assay coefficient of variation was 3%. Patients were categorised as overweight or obese if their BMIs were higher than the 85th or 95th percentile, respectively, for their age and sex as per the Centres for Disease Control and Prevention (CDC) growth charts. 16 One hundred and sixty patients who provided 552 aXa samples The demographics of the population of this study are summarised in Table 1. Figure 1 shows the distribution of age versus weight in the study sample broken down by sex and body size category.

| Evaluation of published models
Two population PK models of enoxaparin in children were identified.
The first described the pharmacokinetics of enoxaparin in children younger than 1 year of age, 17 while the other examined children between 1 and 18 years of age. 5 Both models, described in detail in Appendix S1, were fitted to the data of this study and then evaluated using prediction-corrected visual predictive check (pcVPC) plots to determine model fit to the whole dataset and fit to specific patient subpopulation based on size categories.

| Model building
Data from all 160 patients who met the inclusion criteria were included in the model-building process. Two patients had no recorded value of height or weight. These were imputed with a single imputation from a multivariate distribution of age, sex, weight and height. The root mean squared errors for the imputation of weight and height were 0.854 kg and 11.9 cm, respectively. The final model was re-estimated with the data from patients with missing weight/ height excluded and estimates were compared to the full dataset.
One-and two-compartment models with linear and nonlinear elimination and zero-and first-order absorption were tested to describe the kinetics of aXa activity. Covariates considered on model parameters were postnatal age (Age), postmenstrual age (PMA) (calculated as age + 40 weeks), sex, Wt, BMI, 18 FFM, 19 body surface area (BSA), 20 normal fat mass (NFM), 21 and allometrically scaled Wt and FFM with fixed (0.75 or 0.67) or estimated exponents (see .

T A B L E 1 Demographic characteristics of the study population
where Ht is the height and Ffat is a model parameter that estimates the fractional contribution of fat mass to the NFM.
Continuous covariates were normalised to the population median.
The influence of PMA on the maturation of clearance (CL) was evaluated using the sigmoid hyperbolic maturation function described for maturation of glomerular filtration rate (Equation 6). 22 The covariates were added to the model using forward inclusion backward elimination: Here F age is the fractional clearance adjustment for maturation for a child of a given post-menstrual age (PMA i ), γ is the sigmoidicity coefficient that controls the steepness of the maturation curve (fixed at 3.4 as per Anderson and Holford 22 ) and PMA50 is the age at which clearance is 50% mature (fixed at 47.7 weeks as per Anderson and Holford 22 ).

| Model selection
This analysis was performed in NONMEM v7.4 23  Comparison of the OFV for model selection was based on the likelihood ratio test at the α ¼ 0:05 significance level. Since the difference in the OFV between two nested models is χ 2 -distributed, a difference of 3.84 units was considered equivalent to P = .05 for one degree of freedom.

| Model evaluation
The final model was evaluated using pcVPCs, 25  3 | RESULTS

| Evaluation of published models
The re-estimated published models were able to capture the overall data reasonably well, as shown by the pcVPC (Figure 2). However, when pcVPCs were stratified by body size category, the models showed systematic underprediction of concentrations in overweight/ obese patients which was not evident in the normal-weight group ( Figure 3).

| Population pharmacokinetic model
The data were best described by a one-compartment model with for ω ka , where the CI was relatively wide due to the limited amount of data available in the absorption phase (

| Simulation of dosing regimens
Simulations from the final PK model showed that the current standard of care (SoC) dosing of 1 mg/kg twice daily achieved an overall (in both body size groups) success rate of target attainment of 46.9% after the first dose and 72.6% at steady state. After the first dose, most out-of-range patients (93.8%) had subtherapeutic aXa activities.
Although obese patients had a higher success rate after the first dose under SoC dosing than normal-weight patients (55.7% vs 43.4%), a larger proportion had supratherapeutic aXa activities at steady state (29.5% for overweight/obese vs 9% for normal-weight patients), as illustrated in Table 3 and Figure 6.
These results suggest that the success rate could be optimised by including a loading dose in the regimen to address subtherapeutic aXa activities after the first dose and decreasing the total dose administered to obese/overweight patients. Among the different dosing alternatives tested (see Appendix S4 for more details), the regimen that achieved the highest success rate was 1.8 mg/kg of FFM as the loading dose followed by 1.2 mg/kg of FFM twice daily for maintenance ( Figure 7). This regimen achieves similar aXa activities to the SoC regimen for normal-weight patients at steady state. However, the proposed regimen performs better after the first dose for both normalweight and overweight/obese patients as well as at steady state for overweight/obese patients (see Figure 8). The success rates for FFMbased dosing with the loading dose approach for both normal weight and overweight/obese patients are summarised in Table 3.

| DISCUSSION
This study developed a model to describe the pharmacokinetics of enoxaparin in overweight/obese children. F I G U R E 4 Prediction-corrected visual predictive checks for the final model against the whole dataset. Dashed red lines represent the 10th, 50th and 90th percentiles of observed data. Solid black lines represent the same percentiles of simulated data. Shaded areas represent the 95% CI around the simulated percentiles. Solid black dots represent the observations. Note that observations outside the limits of the time axis are omitted from the plot to enhance the visual interpretability. The limits of the time axis are determined based on the mid-points of the first and last bin assumption that body composition is consistent across weight ranges and therefore clearance would vary proportionally with Wt. However, overweight/obese individuals have less metabolically active lean mass per kilogram of Wt compared to normal-weight individuals and therefore are likely to have less than proportional change in CL with respect to Wt. 6,7 Two population PK models of enoxaparin in children have been published which use allometrically scaled Wt as a covariate on clearance. 5,17 However, when both models were fitted to our dataset and evaluated using pcVPCs overlaid with the data, they performed well overall but significantly underpredicted concentration in the overweight/obese group (see Figure 3). This is probably due to CL This is likely due to the high correlation of patient covariates (eg, age, weight, height and FFM) in this population.
The primary mode of enoxaparin elimination is through glomerular filtration. 29 This suggests that maturation of glomerular filtration rate (GFR) would significantly impact enoxaparin clearance, especially in infants. However, in this analysis, serum creatinine data were not available and therefore an empirical GFR maturation function 22 was used as a covariate on CL but did not achieve any significant improvement in model fitness. This is probably because the FFM calculation includes age therefore summarises the effects of both size and maturation (Equations 1 and 2). In paediatric patients with normal renal function (for size) further adjustment based on impaired renal function was not required.
FFM was also found to be the only significant covariate on V. This is consistent with its high hydrophilicity, which limits distribution to blood, extracellular fluid and highly perfused tissues, 30 which are well represented by FFM. 31 Simulations from the final PK model showed two issues with the current SoC dosing regimen. First, the low rate of target achievement after the first dose with a substantial proportion of patients attaining subtherapeutic aXa activities. Although the overall rate of target attainment is similar to that of adults, 32 plots of simulated data ( Figure 6) show substantial room for improvement. Second, a significantly higher proportion of overweight/obese individuals achieve Based on the proportionality of CL with allometrically scaled FFM, it is expected that patients on the lower end of the FFM range (eg, neonates and infants) require a higher maintenance dose than the recommended regimen. However, this has not been evaluated as it was beyond the scope of this work.
Since enoxaparin is administered subcutaneously, it is expected that obesity and/or maturation may influence on the rate and/or extent of absorption. However, since there were limited observations in the absorption phase, it was not possible to determine such an effect. Although the value of the ka was fixed to the literature value, this value was obtained from studies that were not designed to study the effect of obesity on enoxaparin absorption, and hence misspecification cannot be rolled out. Therefore, an appropriately designed trial can confirm or dispute this and, more importantly, validate the proposed dosing regimen in overweight/obese children.
Of note, the proposed dosing regimen aims to achieve a 4-hour post-dose aXa activity of 0.