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

• Published in: Clinical pharmacokinetics Vol. 63; no. 7; pp. 999 - 1014
• Main Authors: Carreño, Fernando O., Gerhart, Jacqueline G., Helfer, Victória E., Sinha, Jaydeep, Kumar, Karan R., Kirkpatrick, Carl, Hornik, Christoph P., Gonzalez, Daniel
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2024; Springer Nature B.V
• Subjects: Adolescent; Age groups; Anticoagulants; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Body mass index; Body Weight; Child; Child, Preschool; Creatinine; Disease prevention; Dose-Response Relationship, Drug; Drug dosages; Electronic health records; Enoxaparin - administration & dosage; Enoxaparin - pharmacokinetics; Female; Humans; Infant; Infant, Newborn; Internal Medicine; Male; Medicine; Medicine & Public Health; Metadata; Models, Biological; Names; Obesity; Original Research Article; Pediatrics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Precision Medicine - methods; Standard of care
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-024-01388-x

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). 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.