Methodologies for Population Pharmacokinetic Modeling of Target-Site Drug Exposure: A Narrative Review of Current Strategies.

Model-informed precision dosing (MIPD) is increasingly used to guide drug dosing based on population pharmacokinetic (popPK) models developed mainly using plasma concentration data. However, plasma levels may not always correlate well with drug concentrations at the site of action, potentially leading to under- or overestimation of target-site exposure. It is, therefore, important to evaluate which popPK modeling approaches effectively describe drug concentrations at target sites other than plasma to support the selection and implementation of appropriate modeling techniques. This review outlines four general modeling strategies described in literature characterizing the relationship between plasma and target-site drug concentrations. The first approach includes rate constants describing inflow and outflow, which is especially useful for unidirectional transport or large flow rate differences. Second, intercompartmental clearance models capture bidirectional transport with a single parameter that is directly comparable with elimination clearance or blood flow. Third, effect compartment models are used to describe delayed tissue distribution. Lastly, the target site can be modeled as part of either the central or the peripheral compartment. Although therapeutic drug monitoring (TDM) based on target-site concentrations has been suggested, implementation is limited by invasive sampling procedures, limited sample volumes, and the lack of established pharmacokinetic/pharmacodynamic targets. Nevertheless, even small differences in target-site exposure can result in clinical implications, and the applicability of drug monitoring using target-site concentrations has been shown in critically ill patients. In conclusion, target-site concentrations have been successfully predicted using different modeling methodologies and have demonstrated potential to optimize therapy in select clinical cases.