Introduction to PBPK Modelling: Core Concepts for Small and Large Molecules

Physiologically based pharmacokinetic (PBPK) modelling provides the mechanistic frameworks for predicting the absorption, distribution, metabolism, and excretion (ADME) of small- and large-molecule therapeutics, supporting drug development from early discovery through regulatory submission. Although small molecules still constitute the majority of approved drugs, biologics now account for nearly half of the prescription market value, making familiarity with both modelling paradigms essential for DMPK scientists. This review outlines the core structural and mechanistic assumptions of small- and large-molecule PBPK models. Small-molecule models conforming to Lipinski's Rule of Five are typically perfusion-limited, treating organs as well-stirred compartments in which hepatic biotransformation dominates elimination. In contrast, large-molecule models are permeability-limited, incorporating separate vascular, interstitial, and intracellular spaces, with extravasation governed by the two-pore formalism and elimination driven by non-specific macropinocytosis, renal filtration, and target-mediated drug disposition (TMDD). Central to therapeutic antibody disposition is the neonatal Fc receptor (FcRn), whose pH-dependent recycling extends drug half-life and underpins engineering strategies such as pH-switching. We examine differences in dosing, absorption routes, and target repertoires that stem from the drug's physicochemical determinants: molecular weight, charge, and structural rigidity. By outlining these mechanistic distinctions alongside emerging developments, such as permeability-limited models for larger synthetic compounds and biologics-derived targeting modalities, this chapter aims to provide a unified conceptual foundation for applying PBPK modelling across the full spectrum of therapeutic modalities, in support of the Three Pillars of Survival framework linking pharmacokinetics, target engagement, and downstream pharmacology.