Application of structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic model development and evaluation.

This work provides case studies for the pharmacokinetic (PK) analog approach, where a physiologically based pharmacokinetic (PBPK) model for a target chemical (has no PK data) is evaluated using PK data from a source chemical (has existing PK data). A bottom up PBPK modeling approach (using in vitro and in silico inputs) is used to develop human oral PBPK models for caffeine and diphenhydramine. Models are evaluated using in vivo data from structural and functional PK analogs. At the end of the case studies, in vivo PK data for caffeine and diphenhydramine is introduced and both models were able to simulate plasma concentrations which agreed with the in vivo PK data. To further demonstrate that structural analogs can serve as PK analogs, in vitro metabolism and plasma protein binding was compared for a subset of structurally similar ToxCast chemicals and shown to be similar. Next steps for the PK analog approach should focus on evaluating this concept for a broader set of compounds. Using PK analogs for evaluating and establishing confidence in a PBPK model will ensure that PBPK modeling remains a viable option in animal alternative safety assessments.