Search

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. [ABSTRACT FROM AUTHOR]

Dosing guidance for children with obesity is often unknown despite the fact that nearly 20% of US children are classified as obese. Enoxaparin, a commonly prescribed low‐molecular‐weight heparin, is dosed based on body weight irrespective of obesity status to achieve maximum concentration within a narrow therapeutic or prophylactic target range. However, whether children with and without obesity experience equivalent enoxaparin exposure remains unclear. To address this clinical question, 2,825 anti–activated factor X (anti‐Xa) surrogate concentrations were collected from the electronic health records of 596 children, including those with obesity. Using linear mixed‐effects regression models, we observed that 4‐hour anti‐Xa concentrations were statistically significantly different in children with and without obesity, even for children with the same absolute dose (P = 0.004). To further mechanistically explore obesity‐associated differences in anti‐Xa concentration, a pediatric physiologically‐based pharmacokinetic (PBPK) model was developed in adults, and then scaled to children with and without obesity. This PBPK model incorporated binding of enoxaparin to antithrombin to form anti‐Xa and elimination via heparinase‐mediated metabolism and glomerular filtration. Following scaling, the PBPK model predicted real‐world pediatric concentrations well, with an average fold error (standard deviation of the fold error) of 0.82 (0.23) and 0.87 (0.26) in children with and without obesity, respectively. PBPK model simulations revealed that children with obesity have at most 20% higher 4‐hour anti‐Xa concentrations under recommended, total body weight–based dosing compared to children without obesity owing to reduced weight‐normalized clearance. Enoxaparin exposure was better matched across age groups and obesity status using fat‐free mass weight‐based dosing. [ABSTRACT FROM AUTHOR]