Population pharmacokinetics and evaluation of the predictive performance of pharmacokinetic models in critically ill patients receiving continuous infusion meropenem: a comparison of eight pharmacokinetic models.

Background: Several population pharmacokinetic (PopPK) models for meropenem dosing in ICU patients are available. It is not known to what extent these models can predict meropenem concentrations in an independent validation dataset when meropenem is infused continuously. Patients and methods: A PopPK model was developed with concentration-time data collected from routine care of 21 ICU patients (38 samples) receiving continuous infusion meropenem. The predictability of this model and seven other published PopPK models was studied using an independent dataset that consisted of 47 ICU patients (161 samples) receiving continuous infusion meropenem. A statistical comparison of imprecision (mean square prediction error) and bias (mean prediction error) was conducted.
Results: A one-compartment model with linear elimination and creatinine clearance as a covariate of clearance best described our data. The mean ± SD parameter estimate for CL was 9.89 ± 3.71 L/h. The estimated volume of distribution was 48.1 L. The different PopPK models showed a bias in predicting serum concentrations from the validation dataset that ranged from -8.76 to 7.06 mg/L. Imprecision ranged from 9.90 to 42.1 mg/L. Conclusions: Published PopPK models for meropenem vary considerably in their predictive performance when validated in an external dataset of ICU patients receiving continuous infusion meropenem. It is necessary to validate PopPK models in a target population before implementing them in a therapeutic drug monitoring program aimed at optimizing meropenem dosing.