EP-017 - MODEL-INFORMED VANCOMYCIN DOSING TO ADDRESS DELAYED RENAL MATURATION IN INFANTS AND YOUNG CHILDREN WITH CONGENITAL HEART DISEASE.

Y. Shimamoto¹, K. Fukushima², T. Mizuno³, H. Ichikawa¹, K. Kurosaki¹, S. Maeda⁴, M. Okuda⁴; ¹National Cerebral and Cardiovascular, Osaka, Japan, ²Kobe Gakuin University Arise Campus, Kobe, Japan, ³Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ⁴Osaka University, Osaka, Japan.

Background: The pediatric vancomycin (VCM) dosage recommended by IDSA guidelines is 60-80 mg/kg/day when targeting an AUC/MIC ratio of 400-600. However, this dosage frequently results in overexposure in children undergoing operations for congenital heart disease (CHD). This study aimed to determine an appropriate VCM dosing regimen for young children with CHD through population PK modeling and simulations.

Methods: A total of 1,254 VCM serum concentrations from postoperative 152 patients (3 days - 13 years old) were available for analysis. eGFR was estimated using the updated Schwartz equation [Zhang et al. CPT 2021]. Population PK analysis was performed with Phoenix NLME 8.3. The effect of growth and maturation on VCM clearance was described by allometrically scaled body weight and a sigmoidal maturation function using postmenstrual age (PMA), respectively. The developed PK model was used for simulation analyses to evaluate the achievement of a target of 400 ≤ AUC/MIC ≤ 600 to determine optimal dosing regimens.

Results: Body weight and height in 74% and 64% of patients are < 5 percentiles in the CDC growth charts. The eGFR, body weight, and PMA were identified as significant covariates. The hill coefficient estimate in this study (1.49) was lower than the previously reported value for GFR (3.40), indicating the delayed maturation of renal function. The identified VCM doses to reach 400 ≤ AUC/MIC ≤ 600 for age ≤ 3 months (median eGFR 40 mL/min/1.73m2) and 3 months < age ≤ 3 years (median eGFR 60 mL/min/1.73m2) were 25 mg/kg/day and 35 mg/kg/day, respectively.

Conclusion: This study indicates the delayed maturation of VCM clearance in postoperative young children with CHD, possibly due to cyanosis and low cardiac output. The model-informed simulations identified the lower VCM doses for this population.