Physiologically Based Pharmacokinetic (PBPK) Modeling of Antidepressants: A Scoping Review of Existing Models, Applications, and Software Tools.

Abstract

Physiologically based pharmacokinetic models are a valuable tool for simulating antidepressant pharmacokinetics in patient groups that are often underrepresented in clinical trials. Clinical data on antidepressant use in vulnerable populations such as geriatric patients or pregnant women remain limited, making safe and personalized treatment challenging. The objective of this review was to systematically evaluate existing physiologically based pharmacokinetic models for antidepressants, their applications, and the modeling software platforms used, in order to identify relevant research gaps and highlight future needs for model development. A scoping review was conducted in accordance with Preferred Reporting Items for Scoping Reviews (PRISMA-ScR) guidelines. Seven electronic databases were systematically searched. Data on the modeled drug, model applications, and software platforms were extracted and evaluated. A total of 60 studies met the inclusion criteria. The availability of physiologically based pharmacokinetic models across antidepressants was heterogeneous. Paroxetine, fluvoxamine, and venlafaxine were most frequently modeled (n = 10 each), whereas few or no models exist for substances such as mirtazapine (n = 1) or milnacipran (n = 0). The main application areas were drug-drug interactions (n = 18), pregnancy (n = 14), and drug-(drug-)gene interactions (n = 13). Pediatric populations and specific ethnic groups were rarely addressed. SimCyp® Simulator was the most used modeling platform, followed by PK-Sim®/Mobi®, GastroPlus®, and R®/RStudio®. Although physiologically based pharmacokinetic models for antidepressants are increasingly available, they focus on a limited number of drugs and applications. Substantial evidence gaps remain, particularly for vulnerable patient populations.