Table 1.

Application-specific model parameters needed for PBPK model development using a middle-out approach

Broad category of PBPK application	Specific purpose of PBPK model	Typical parameters needed for PBPK model development in a middle-out approach
		Sourced from in vitro experiments	Sourced from clinical data
Absorption/formulation	Effects of food and proton pump inhibitors on absorption, bioequivalence or relative bioavailability	Biorelevant solubility Dissolution Permeability Fraction metabolized in gut	CL (IV) for a high CL compound that is expected to have gut extraction
Exposure prediction in a target population: extrapolation from a base population (usually a healthy adult Caucasian) to other populations	Other populations: pediatric, geriatric, obese, smoker, organ-impaired, pregnant, PGX, ethnicity	Knowledge of differences in contributing pathways from the base population (fm,CYP in the base and target populations) In vitro data related to the metabolic pathways that are unique to the target population Plasma protein binding (fu) in both the base and target population Blood plasma partitioning (R)	CL, Vss (IV) ADME
DDI involving enzymes	Drug as a victim Drug as a perpetrator	Parameters related to pathway characterization Plasma protein binding (fu) Blood plasma partitioning (R) Efficacious dose Reversible inhibition (Ki) TDI (KI, kinact), and Induction (EC50, Emax) Plasma protein binding (fu) If the affected isoform of the enzyme also metabolizes the inhibitor fm,isoform,organ to account for auto-inhibition/induction	CL, Vss (IV) ADME CLpo Fraction absorbed, fabs and gut bioavailability (Fg), if the affected isoform of the enzyme metabolizes the inhibitor and is expressed in the gut
DDI involving transporters	Drug as a victim Drug as a perpetrator	In vivo relevance of transporter in addition to those needed for DDI involving enzymes In vitro data for reversible transporter inhibition (Ki) in addition to those needed for DDI involving enzymes	CL, Vss (IV) ADME CLpo

ADME absorption, distribution, metabolism and elimination, CL clearance, DDI drug–drug interaction, EC₅₀ half maximal effective concentration, E_max maximum effective concentration, f_abs fraction absorbed, F_g gut bioavailability, f_{m,isoform,organ}, fraction metabolized by an enzyme isoform in the organ of interest, f_u fraction unbound in plasma, IV intravenous, K _ireversible inhibition constant, K_I inhibitor concentration at half maximal inactivation, k_inact maximal enzyme inactivation rate constant, PBPK physiologically based pharmacokinetic, R blood-plasma ratio, V_ss volume of distribution at steady state, CL_po oral clearance