Table 2.

Clinical data sources for PBPK model development, verification and validation

Application	Clinical data used for model development, parameter estimation, verification	Data for model validation
Absorption: modified release formulation development	Model built with IR human PK in the fed and fasted states	Model simulations of CR validated in monkey
Exposure prediction in a target population	PK of the base population from a SAD and a MAD ADME mass balance, fm, fm,CYP fu in both the base and target population	Target population is qualified Pathway validation from DDI studies in the base population
PK prediction of an untested dose/regimen	Single dose PK from a SAD Repeated dose PK from a MAD
DDI: NCE is a victim drug coadministered with a weak/moderate inhibitor	PK of the victim drug from a SAD and a MAD ADME mass balance fm, fm,CYP	PK of the victim drug coadministered with and without a strong inhibitor
DDI: NCE is a perpetrator of an enzyme isoform that is not involved in its metabolism	PK of a perpetrator drug from a SAD and MAD In vitro Ki	Model able to recover an observed interaction of NCE with a sensitive substrate
DDI: NCE is a perpetrator of an enzyme isoform that is involved in its own metabolism	PK of a perpetrator drug from SAD In vitro Ki fm,CYP of inhibited isoform	Model able to recover an observed interaction of NCE with a sensitive substrate

ADME absorption, distribution, metabolism and elimination, CR controlled release, DDI drug–drug interaction, fm fraction metabolized, fm,CYP fraction metabolized by CYP isoform, fu fraction unbound in plasma, IR immediate release, Ki inhibition constant, MAD multiple ascending dose, NCE new chemical entity, PK pharmacokinetics, SAD single ascending dose