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Model-Informed Vancomycin Dosing Optimization to Address Delayed Renal Maturation in Infants and Young Children with
Yuko Shimamoto1,2, Keizo Fukushima3, Tomoyuki Mizuno3,4
1Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Insights
Children with critical congenital heart disease (CCHD) show delayed kidney maturation, leading to vancomycin (VCM) overexposure. New VCM dosing regimens are proposed to ensure safe and effective drug therapy in this vulnerable population.
Area of Science:
- Pharmacokinetics and pharmacodynamics
- Pediatric pharmacology
- Congenital heart disease research
Background:
- Infants and children require tailored drug dosing due to growth and organ development.
- Data on organ function maturation in special pediatric populations, like those with congenital diseases, are limited.
- Standard vancomycin (VCM) pediatric dosing often leads to overexposure in children with critical congenital heart disease (CCHD).
Purpose of the Study:
- To characterize vancomycin (VCM) clearance maturation in pediatric patients with critical congenital heart disease (CCHD).
- To determine appropriate VCM dosing regimens for CCHD patients using population pharmacokinetic (PK) modeling and simulations.
- To address the scarcity of organ function maturation data in special pediatric populations.
Main Methods:
- Population pharmacokinetic (PK) analysis of 1,254 VCM serum concentrations from 152 postoperative patients (3 days–13 years).
- Development of a two-compartment PK model incorporating allometrically scaled body weight, estimated glomerular filtration rate (eGFR), and postmenstrual age as covariates.
- Simulation analyses to determine optimal VCM doses based on age and eGFR.
Main Results:
- Observed VCM clearance was 33% lower in patients ≤1 year and 40% lower in patients 1-2 years compared to non-CCHD patients.
- This indicates delayed renal maturation in pediatric patients with CCHD, potentially due to cyanosis and low cardiac output.
- Simulation-derived VCM doses: 25 mg/kg/day for age ≤3 months and 35 mg/kg/day for 3 months < age ≤3 years, with specific eGFR considerations.
Conclusions:
- Children with CCHD exhibit delayed renal maturation, impacting VCM pharmacokinetics.
- Model-informed simulations identified significantly lower VCM doses compared to standard pediatric guidelines.
- This study provides crucial data for optimizing vancomycin therapy in pediatric CCHD patients, enhancing drug safety and efficacy.
Abstract:
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.
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