Evaluation of Neonatal and Paediatric Vancomycin Pharmacokinetic Models and the Impact of Maturation and Serum Creatinine Covariates in a Large Multicentre Data Set

Background And Objective: Infants and neonates present a clinical challenge for dosing drugs with high interindividual variability due to these patients' rapid growth and the interplay between maturation and organ function. Model-informed precision dosing (MIPD), which can account for interindividual variability via patient characteristics and Bayesian forecasting, promises to improve individualized dosing strategies in this complex population. Here, we assess the predictive performance of published population pharmacokinetic models describing vancomycin in neonates and infants, and analyze the robustness of these models in the face of clinical uncertainty surrounding covariate values.

Methods: The predictive precision and bias of nine pharmacokinetic models were compared in a large multi-site data set (N = 2061 patients, 5794 drug levels, 28 institutions) of patients aged 0-365 days. The robustness of model predictions to errors in serum creatinine measurements and gestational age was assessed by using recorded values or by replacing covariate values with 0.3, 0.5 or 0.8 mg/dL or with 40 weeks, respectively.

Results: Of the nine models, two models (Dao and Jacqz-Aigrain) resulted in predicted concentrations within 2.5 mg/L or 15% of the measured values for at least 60% of population predictions. Within individual models, predictive performance often 2 differed in neonates (0-4 weeks) versus older infants (15-52 weeks). For preterm neonates, imputing gestational age as 40 weeks reduced the accuracy of model predictions. Measured values of serum creatinine improved model predictions compared to using imputed values even in neonates ≤1 week of age.

Conclusions: Several available pharmacokinetic models are suitable for MIPD in infants and neonates. Availability and accuracy of model covariates for patients will be important for guiding dose decision-making.