Building confidence in PBK model predictions in the absence of human kinetic data: Benzophenone-4 case study

This study aimed to develop a physiologically based kinetic (PBK) model for benzophenone-4 (BP-4) in humans based on in vitro and in silico input data and to achieve scientific confidence in predicted internal exposures of BP-4 in the absence of human kinetic data. The key steps included are: 1) establishing a core PBK model containing minimal required input for dermal absorption, liver metabolism, plasma protein binding, blood:plasma ratio, and tissue:plasma partition coeffi­cients, 2) using chemical-specific characteristics to define additional key kinetic processes, which led to inclusion of transporter kinetics, and 3) conducting sensitivity analyses and assessing popu­lation variability. The in vitro kinetic results revealed limited skin penetration of BP-4 (< 0.4%), no metabolic conversion by the liver, and involvement of active transporters, including OAT1, OAT2, OAT3, BCRP, and MRP4. Inclusion of the transporter activity in the PBK model (scaled to kidney and liver) resulted in BP-4 active excretion and lowering of the plasma concentrations from 4 μM to 0.7 μM. Due to faster influx rates, by OAT1, OAT2, and OAT3, compared to efflux rates by BCRP and MRP4, relatively higher organ concentrations were predicted for the liver (0.31 μM) and kidney (0.18 μM) compared with other organs. While the PBK model results could not be evaluated against human data, we could evaluate the evolution of predicted concentrations in the process of developing the model. Increasing the physiological relevance of the model through inclusion of transporters increased confidence in the plausible ranges in plasma and organ concentrations.