Characterizing Enoxaparin's Population Pharmacokinetics to Guide Dose Individualization in the Pediatric Population

Abstract

Background and objective: Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct. METHODS: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0-18 years, TBW) or fat-free mass (2-18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity.

Results: A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied.

Conclusion: Using real-world data and PopPK modeling, enoxaparin's pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity.

Fig. 1

Anti-Xa plasma concentration (IU/mL) versus time after enoxaparin dose stratified by post-natal age groups. Concentrations are displayed using (A) linear and (B) semi- logarithmic scales. The symbols represent four age groups plotted.

Fig. 2

Goodness-of-fit plots for the final population pharmacokinetic model. (A) Observed anti-Xa concentrations versus population predictions. (B) Observed versus individual predictions. (C) Conditional weighted residuals (CWRES) versus population predictions. (D) CWRES versus postnatal age in years. In plots (A) and (B) the grey line represents the line of identity and plots (C) and (D) the grey line represents the zero-slope line. In all plots the dashed red line is the local polynomial regression fitting (LOESS). The predicted and observed anti-Xa concentrations are in IU/mL.

Fig. 3

Population pharmacokinetic model simulated anti-Xa 4-h concentration at steady state following twice-daily subcutaneous daily dosing of 0.7 – 1.5 mg/kg (treatment doses) using total body weight (TBW, left plots) or fat-free mass (FFM according to the Al-Sallami et al. equation, right plots) for virtual children 2 to < 6 years, 6 to < 12 years, and ≥ 12 years of age (n = 1,000 virtual children per age group). The boxes represent the median and interquartile range (IQR), and the whiskers extend to 1.5 × IQR. The red dashed lines represent the target ranges for treatment (0.6 –1.0 IU/mL) dosing. Similar plots are represented in Supplementary Fig. 14 of the Electronic Supplementary Materials (ESM) for prophylaxis doses (0.2 – 0.6 mg/kg) and Supplementary Fig. 15 of the ESM for once-daily daily dosing regimens.

Fig. 4

The percentage of simulated patients with an enoxaparin 4-h concentration below (blue), within (green), and above (red) the recommended ranges for treatment (0.6 – 1.0 IU/mL for twice daily dosing – top left, and 1.0 – 2.0 IU/mL for once daily dosing – top right) or prophylaxis (0.1–0.3 IU/mL, bottom) following twice daily subcutaneous dosing of 1 mg/kg (top left), once daily subcutaneous dosing of 2 mg/kg (top right), twice daily subcutaneous dosing of 0.5 mg/kg (bottom left), or once daily subcutaneous dosing of 1 mg/kg (bottom right) using total body weight (TBW, left bars) or fat-free mass (FFM calculated according to the Al-Sallami et al. equation, right bars) for children ages 2 to 18 years (n = 3,000 virtual children per group).

Fig. 5

Population pharmacokinetic model simulated anti-Xa 4-h concentration following once or twice-daily subcutaneous total daily dosing of 0.4 – 3.0 mg/kg using total bodyweight (TBW) for children < 1 month, 1 to < 6 months, 6 to < 12 months, and 1 to < 2 years of age (n = 1,000 virtual children per group). The boxes represent the median and interquartile range (IQR), and the whiskers extend to 1.5 × IQR. The orange, red, and blue dashed lines represent the target ranges for treatment with once-daily dosing (1.0 – 2.0 IU/mL), for treatment with twice-daily dosing (0.6 – 1.0 IU/mL), and prophylaxis dosing (0.1 – 0.3 IU/mL), respectively.