A Model Averaging/Selection Approach Improves the Predictive Performance of Model-Informed Precision Dosing: Vancomycin as a Case Study

Abstract

Many important drugs exhibit substantial variability in pharmacokinetics and pharmacodynamics leading to a loss of the desired clinical outcomes or significant adverse effects. Forecasting drug exposures using pharmacometric models can improve individual target attainment when compared with conventional therapeutic drug monitoring (TDM). However, selecting the "correct" model for this model-informed precision dosing (MIPD) is challenging. We derived and evaluated a model selection algorithm (MSA) and a model averaging algorithm (MAA), which automates model selection and finds the best model or combination of models for each patient using vancomycin as a case study, and implemented both algorithms in the MIPD software "TDMx." The predictive performance (based on accuracy and precision) of the two algorithms was assessed in (i) a simulation study of six distinct populations and (ii) a clinical dataset of 180 patients undergoing TDM during vancomycin treatment and compared with the performance obtained using a single model. Throughout the six virtual populations the MSA and MAA (imprecision: 9.9-24.2%, inaccuracy: less than ± 8.2%) displayed more accurate predictions than the single models (imprecision: 8.9-51.1%; inaccuracy: up to 28.9%). In the clinical dataset, the predictive performance of the single models applying at least one plasma concentration varied substantially (imprecision: 28-62%, inaccuracy: -16 to 25%), whereas the MSA or MAA utilizing these models simultaneously resulted in unbiased and precise predictions (imprecision: 29% and 30%, inaccuracy: -5% and 0%, respectively). MSA and MAA approaches implemented in TDMx might thereby lower the burden of fit-for-purpose validation of individual models and streamline MIPD.