Systematic Evaluation of Voriconazole Pharmacokinetic Models without Pharmacogenetic Information for Bayesian Forecasting in Critically Ill Patients

Abstract

Voriconazole (VRC) is used as first line antifungal agent against invasive aspergillosis. Model-based approaches might optimize VRC therapy. This study aimed to investigate the predictive performance of pharmacokinetic models of VRC without pharmacogenetic information for their suitability for model-informed precision dosing. Seven PopPK models were selected from a systematic literature review. A total of 66 measured VRC plasma concentrations from 33 critically ill patients was employed for analysis. The second measurement per patient was used to calculate relative Bias (rBias), mean error (ME), relative root mean squared error (rRMSE) and mean absolute error (MAE) (i) only based on patient characteristics and dosing history (a priori) and (ii) integrating the first measured concentration to predict the second concentration (Bayesian forecasting). The a priori rBias/ME and rRMSE/MAE varied substantially between the models, ranging from −15.4 to 124.6%/−0.70 to 8.01 mg/L and from 89.3 to 139.1%/1.45 to 8.11 mg/L, respectively. The integration of the first TDM sample improved the predictive performance of all models, with the model by Chen (85.0%) showing the best predictive performance (rRMSE: 85.0%; rBias: 4.0%). Our study revealed a certain degree of imprecision for all investigated models, so their sole use is not recommendable. Models with a higher performance would be necessary for clinical use.

Keywords

• precision medicine
• antifungal
• model informed precision dosing
• pharmacokinetics
• therapeutic drug monitoring
• voriconazole