External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings

Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings.

Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of 6 models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics (visual predictive check [VPC] and normalized prediction distribution errors [NPDE]).

Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for 6 evaluated models were 1.35, -0.22, -0.36, 0.24, 0.66, 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still need to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin.

The importance of analytical techniques for serum creatinine concentrations and vancomycin as a predictor of vancomycin concentrations in neonates has been confirmed. Dosage individualisation of vancomycin in neonates should consider not only patients’ characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin.