Assessment of Piperacillin–Tazobactam Population Pharmacokinetic Models in Neonates: An External Validation

Background and Objective: Neonatal pharmacotherapy has gained attention from clinicians and regulatory agencies for optimizing the dosage of the drug which improves therapeutic outcomes in this special population. Piperacillin–tazobactam antibiotic is commonly used as a therapeutic option for treatment of severe infection in neonatal intensive care units. There are few population pharmacokinetic (PopPK) studies of piperacillin and tazobactam published for this specific population and which were not validated in other study settings. The aim of this study was to externally evaluate the published population pharmacokinetic models for piperacillin–tazobactam. Methods: A systematic review was conducted through Scopus, PubMed, and Embase databases to identify PopPK models. Clinical data collected in neonates treated with piperacillin–tazobactam were used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions. Results: Three PopPK models were identified for external evaluation. A total of 53 plasma samples were collected from 46 neonates admitted in the neonatal intensive care unit. The PopPK models reported by Cohen-Wolkowiez et al. for piperacillin and Li et al. for tazobactam were able to predict well for our clinical data. Conclusion: The PopPK models by Cohen-Wolkowiez et al. and Li et al. predicted our data well for piperacillin and tazobactam with the lower relative median absolute predictive error (rMAPE) of 8.61% and 16.48% and relative root mean square error (rRMSE) of 0.01 and 0.03, respectively. External evaluation of the published PopPK models of piperacillin and tazobactam resulted in enhancing their credibility to be implemented in clinical practice.