Evaluation and Improvement of Specialized Vancomycin Pharmacokinetic Models for Pediatric Cardiovascular Intensive Care Unit and Pediatric Oncology Patients.
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BACKGROUND AND OBJECTIVE: Dose optimization of vancomycin in distinct pediatric subpopulations is inherently complex due to altered vancomycin pharmacokinetics associated with certain conditions or circumstances, such as cancer or postoperative cardiac surgery. Numerous population pharmacokinetic models have been developed that aim to capture these alterations; however, it is currently unclear whether these specialized models are necessary, or if covariates in a well-specified general model can adequately capture pharmacokinetic variation between special subpopulations. Here, we conduct an external evaluation comparing the predictive performance of published general and specialized population pharmacokinetic models in pediatric oncology and pediatric cardiovascular intensive care unit (CVICU) patients in order to address this question, and guide model selection decisions for model-informed precision dosing of vancomycin in these subpopulations. METHODS: The predictive error, bias, and accuracy of two general, six oncology-supporting, and three CVICU-supporting pharmacokinetic models were compared in two multi-site data sets of pediatric oncology (N = 371, 1392 drug levels, 20 sites) and pediatric CVICU (N = 219, 1136 drug levels, 11 sites) patients, respectively. The best performing model(s) in each subpopulation were refit to evaluate whether predictive performance could be further improved over the published models. RESULTS: We find that although specialized models performed better than general population models for pediatric CVICU patients, a general model (Colin 2019) performed better than all specialized models for pediatric oncology patients. We additionally report a refit version of the Shimamoto 2024 model for pediatric CVICU patients, which performed better than all published CVICU-supporting models in our data set. CONCLUSION: Population pharmacokinetic models developed on distinct pediatric subpopulations are not necessarily more fit-for-purpose than models developed on a general population. Both well-specified general models and specialized models may be capable of achieving suitable clinical performance in these subpopulations, and this assessment of model fit-for-purpose must be made on a case-by-case basis.