Model‐Informed Vancomycin Dosing Optimization to Address Delayed Renal Maturation in Infants and Young Children with Critical Congenital Heart Disease

• Published in: Clinical pharmacology and therapeutics 2024-02, Vol.115 (2), p.239-247
• Main Authors: Shimamoto, Yuko, Fukushima, Keizo, Mizuno, Tomoyuki, Ichikawa, Hajime, Kurosaki, Kenichi, Maeda, Shinichiro, Okuda, Masahiro
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents; Child; Child, Preschool; Glomerular Filtration Rate; Heart Defects, Congenital - drug therapy; Heart Defects, Congenital - surgery; Humans; Infant; Kidney; Vancomycin
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.3095

Ensuring safe and effective drug therapy in infants and young children often requires accounting for growth and organ development; however, data on organ function maturation are scarce for special populations, such as infants with congenital diseases. Children with critical congenital heart disease (CCHD) often require multiple staged surgeries depending on their age and disease severity. Vancomycin (VCM) is used to treat postoperative infections; however, the standard pediatric dose (60–80 mg/kg/day) frequently results in overexposure in children with CCHD. In this study, we characterized the maturation of VCM clearance in pediatric patients with CCHD and determined the appropriate dosing regimen using population pharmacokinetic (PK) modeling and simulations. We analyzed 1,254 VCM serum concentrations from 152 postoperative patients (3 days–13 years old) for population PK analysis. The PK model was developed using a two‐compartment model with allometrically scaled body weight, estimated glomerular filtration rate (eGFR), and postmenstrual age as covariates. The observed clearance in patients aged ≤ 1 year and 1–2 years was 33% and 40% lower compared with that of non‐CCHD patients, respectively, indicating delayed renal maturation in patients with CCHD. Simulation analyses suggested VCM doses of 25 mg/kg/day (age ≤ 3 months, eGFR 40 mL/min/1.73 m2) and 35 mg/kg/day (3 months < age ≤ 3 years, eGFR 60 mL/min/1.73 m2). In conclusion, this study revealed delayed renal maturation in children with CCHD, could be due to cyanosis and low cardiac output. Model‐informed simulations identified the lower VCM doses for children with CCHD compared with standard pediatric guidelines.