Table 1.

Summary of PBPK modeling approaches and their applications

Modeling approach	Data availability	Examples of modeling scenarios	General applications
Bottom‐up	Physiochemical properties and blood binding (LogP, pKa, fup, B/P)	Projection of human drug distribution	Provide mechanistic understanding
	In vitro permeability and pharmaceutics information	Projection of human PK parameters and FIH dose
	In vitro metabolism and transporters substrate data	Enzyme/transporter DDI projection (victim and perpetrator)
	In vitro metabolism and transporters perpetrator data
	In vivo ADME information in preclinical species
Top‐down	Clinical concentration‐time profiles from single or multiple ascending doses with summary of PK parameters	Development of model and identify parameters and their intersubject variability as well as identifying covariates	Support clinical trial decisions
Middle‐out	Physiochemical properties and in vitro ADME data may be available, but key in vitro quantitative or mechanistic data may be lacking	Refined predictions of DDI (perpetrator or victim)	Provide mechanistic understanding and support clinical trial decisions
	Clinical concentration‐time profiles after single and multiple ascending doses with summary of PK parameters	Special populations (pediatrics, organ impairment),
	May have clinical DDI data available as a victim and/or perpetrator for key CL pathway(s)	Formulation optimization or selection; in silico bioequivalence
	In vivo human ADME or mass‐balance data