From Therapeutic Drug Monitoring to Model-Informed Precision Dosing for Anti-Infectives

Critically ill patients, who often suffer from infections caused by less susceptible bacteria, exhibit altered and highly variable pharmacokinetics (PK). Therapeutic Drug Monitoring (TDM) has long been used to personalize dosing in this patient group for several drugs such as vancomycin and aminoglycosides. Recently, the use of pharmacometric models has gained significant interest to enhance the TDM, a process referred to as “model-informed precision dosing” (MIPD). Using MIPD in clinical practice can streamline the TDM process, but also requires careful validation and training before adoption. The presentation will highlight the importance of systematic model validation using several examples (vancomycin, piperacillin, meropenem, linezolid). An automated model selection/averaging algorithm will be presented that has shown to improve the predictive performance in several settings, and eliminated the need to individually select a model for each patient. While the focus for TDM traditionally lays on PK, biomarkers such as C-reactive protein (CRP) or procalcitonin are frequently available, but not interpreted together with the TDM sample. Recent work on a joint pharmacometric model that linked the vancomycin PK with CRP kinetics and its forecasting performance in the MIPD setting will be presented. Lastly, clinical trials to demonstrate the benefit of MIPD at bedsite are required. Some evidence from the literature is reviewed and experience on how to setup a randomized controlled pilot trial at the University Medical Centre Hamburg-Eppendorf for MIPD of linezolid will be shared.