Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency
Jennifer Le1, Florin Vaida2, Emily Nguyen3
1University of California San Diego, La Jolla, CA ; Miller Children's Hospital, Long Beach, CA.
Insights
Vancomycin dosing for children with kidney problems needs careful adjustment. A dose of 45 mg/kg/day may be suitable for some, but monitoring is crucial due to changing renal function.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Nephrology
- Infectious Diseases
Background:
- Achieving the target vancomycin area-under-the-curve to minimum inhibitory concentration (AUC/MIC) ratio of ≥ 400 in pediatric patients with renal insufficiency is not well-established.
- Understanding vancomycin clearance (CL) and optimal initial dosing in children with normal versus impaired renal function is critical for effective treatment.
Purpose of the Study:
- To compare vancomycin clearance (CL) and initial dosing requirements in pediatric patients with normal renal function versus those with renal insufficiency.
- To identify key covariates influencing vancomycin CL in children.
Main Methods:
- A matched case-control study design was employed, including pediatric patients aged ≥ 3 months receiving vancomycin for ≥ 48 hours.
- Population pharmacokinetic modeling with empiric Bayesian post-hoc individual parameter estimation and Monte Carlo simulations were utilized.
- Cases (baseline serum creatinine [SCr] ≥ 0.9 mg/dL) were matched 1:1 to controls based on age and weight.
Main Results:
- The final model identified age, SCr, and weight as independent covariates for vancomycin CL. The formula derived was: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19, with an inter-subject variability (ISV) of 39%.
- A vancomycin dose of 45 mg/kg/day achieved the target AUC/MIC ≥ 400 in 80% of cases with renal impairment, whereas controls required 60 mg/kg/day.
- Renal function recovery led to improved vancomycin CL in 87% of cases during therapy.
Conclusions:
- Reduced vancomycin CL in pediatric patients with renal impairment suggests that a less frequent dosing regimen of 15 mg/kg every 8 hours (45 mg/kg/day) may be appropriate for some.
- Close monitoring of renal function and vancomycin concentrations is essential to ensure therapeutic drug exposure, particularly in patients with renal impairment where function may recover during treatment.
Background:
Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function.
Methods:
Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight.
Results:
Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function.
Conclusion:
Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.
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