Can PBPK Modeling Improve Compound Optimization and Medicinal Chemistry Decision-Making in Complex Chemical Space?

As drug discovery increasingly explores beyond-rule-of-five compounds and challenging classical small molecules such as zwitterionic, highly lipophilic, and tissue-targeted drugs, pharmacokinetic behavior is more often governed by interactions with physicochemical and biological processes that limit the utility of purely empirical optimization approaches. In this Perspective, we discuss the role of physiologically based pharmacokinetic (PBPK) modeling as a mechanistic framework for understanding complex drug disposition and enabling model-informed decision-making during early stages of drug discovery by integrating early in vivo data, literature-derived compounds, and sensitivity and uncertainty analysis.