Population pharmacokinetics of vancomycin and AUC-guided dosing in Chinese neonates and young infants

Abstract

Objectives

To develop a population pharmacokinetic (PK) model for vancomycin in Chinese neonates and infants less than 2 months of age (young infants) with a wide gestational age range, in order to determine the appropriate dosing regimen for this population.

Methods

We performed a retrospective chart review of patients from the neonatal intensive care unit (NICU) at Children’s Hospital of Fudan University to identify neonates and young infants treated with vancomycin from May 2014 to May 2017. Vancomycin concentrations and covariates were utilized to develop a one-compartment model with first-order elimination. The predictive performance of the final model was assessed by both internal and external evaluation, and the relationship between trough concentration and AUC_0–24 was investigated. Monte Carlo simulations were performed to design an initial dosing schedule targeting an AUC_0–24 ≥ 400.

Results

The analysis included a total of 330 concentration–time data points from 213 neonates and young infants with gestational age (GA) and body weight of 25–42 weeks and 0.88–5.1 kg, respectively. Body weight, postmenstrual age (PMA) and serum creatinine level were found to be important factors explaining the between-subject variability in vancomycin PK parameters for this population. Both internal and external evaluation supported the prediction of the final vancomycin PK model. The typical population parameter estimates of clearance and distribution volume for an infant weighing 2.73 kg with a PMA of 39.8 weeks and serum creatinine of 0.28 mg/dL were 0.103 L/h/kg and 0.58 L/kg, respectively. Although vancomycin serum trough concentrations were predictive of the AUC, considerable variability was observed in the achievement of an AUC_0–24/MIC of ≥400. For MIC values of ≤0.5 mg/L, AUC_0–24/MIC ≥400 was achieved for 95% of the newborn infants with vancomycin troughs of 5–10 mg/L. When the MIC increased to 1 mg/L, only 15% of the patients with troughs of 5–10 mg/L achieved AUC_0–24/MIC ≥400. For MIC values of 2 mg/L, no infants achieved the target. Simulations predicted that a dose of at least 14 and 15 mg/kg every 12 h was required to attain the target AUC_0–24 ≥ 400 in 90% of infants with a PMA of 30–32 and 32–34 weeks, respectively. This target was also achieved in 93% of simulated infants in the oldest PMA groups (36–38 and 38–40 weeks, respectively) when the dosing interval was extended to 8 h. For infants with a PMA ≥44 weeks, a dose increase to 18 mg/kg every 8 h was needed. The trough concentrations of 5–15 mg/L were highly predictive of an AUC_0–24 of ≥400 when treating invasive MRSA infections with an MIC of ≤1 mg/L.

Conclusions

The PK parameters for vancomycin in Chinese infants younger than 2 months of age were estimated using the model developed herein. This model has been used to predict individualized dosing regimens in this vulnerable population in our hospital. A large external evaluation of our model will be conducted in future studies.