From Therapeutic Drug Monitoring to Model‐Informed Precision Dosing for Antibiotics

Abstract

(ISAP), the PK/PD study group of the European Society of Clinical Microbiology, Infectious Diseases (EPASG) Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended.

Pharmacokinetics of Antibiotics in Pediatric Intensive Care: Fostering Variability to Attain Precision Medicine

“…Still, none of these studies investigated a clinical primary endpoint, nor was the cost-effectiveness of an MIPD strategy evaluated. In adults, several retrospective or small clinical trials have suggested a clinical benefit from antibiotic TDM, with or without MIPD [186]. Recently, preliminary results of the TARGET trial, a large multicenter randomised controlled trial (RCT) in 10 German ICUs, failed to show a clinical benefit from TDM-guided dosing of piperacillin-tazobactam in critically ill adults [187].…”

Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice

“…The main flaw of traditional TDM is the existence of a reference range of concentrations instead of one target concentration, which means that a clinician's decision making is driven by experience, rather than evidence-based facts (71,76). Moreover, samples should be taken from patients after steady state is achieved (77). One way to overcome the disadvantages of classical TDM is to use approaches that take into account the drug, disease, and patient characteristics, such as the model informed drug precision approach (MIPD) (78).…”

“…One way to overcome the disadvantages of classical TDM is to use approaches that take into account the drug, disease, and patient characteristics, such as the model informed drug precision approach (MIPD) (78). In this approach, TDM data, together with the individual patient's demographic, pharmacogenetic, clinical and therapy characteristics, are interpreted using the population model (31,77,79). Even before the administration of the first dose, the developed model can be used to calculate population parameters considering covariates for the specific patient and propose dosage regimen based on these estimates.…”

“…It uses prior information about population model parameters and their uncertainties together with measured drug concentrations and individual covariates to maximize the probability of individual parameter values (maximum a posteriori Bayesian estimate). Consequently, the estimated individual parameters are further used for more precise dosage regimen optimisation (56,77,81). Moreover, simulations can be performed based on the individual PK parameters, to obtain a dosing regimen that maximizes the achievement of the target (77).…”

“…Consequently, the estimated individual parameters are further used for more precise dosage regimen optimisation (56,77,81). Moreover, simulations can be performed based on the individual PK parameters, to obtain a dosing regimen that maximizes the achievement of the target (77). Due to the complexity of NONMEM software in routine clinical practice, new tools are being developed (82).…”