Figure 2.

Comparison of PK model-adjustment performance: injection dosing. The performance of 8 PK model-adjustment combinations (detailed in Methods and below) was compared using root mean squared error (RMSE) (A) and mean residual values (MRV) (B) between $\mathrm{lo}{\mathrm{g}}_{10}$ values of EAD and median LELs from uterotrophic injection studies, calculated for three groups of chemicals: all 29 chemicals (asterisk), 13 chemicals with experimental values for ${\mathrm{f}}_{\mathrm{u}}$ and ${\text{CL}}_{\text{int}}$ (EE, triangle symbol), and 14 chemicals where QPPR and QSAR models were used to predict both ${\text{CL}}_{\text{int}}$ and ${\mathrm{f}}_{\mathrm{u}}$, respectively (QQ, circle symbol). PPK, one-compartment population-based pharmacokinetic model; ${\text{HT}3\mathrm{C}}_{\text{inj}}$, the httk “3compartment” model simulating injection exposure route; ${\text{GP}}_{\text{inj}}$, PBPK model built using GastroPlus™ software simulating injection exposure route. PPK_EF, ${\text{HT}3\mathrm{C}}_{\text{inj}}\_\text{EF}$, ${\text{GP}}_{\text{inj}}\_\text{EF}$ are corresponding PPK, ${\text{HT}3\mathrm{C}}_{\text{inj}}$ and ${\text{GP}}_{\text{inj}}$ models with EF adjustment applied for ${\text{ACC}}_{\text{ER}}$. $\text{PPK}\_{\mathrm{f}}_{\mathrm{u}}$ is PPK model with ${\mathrm{f}}_{\mathrm{u}}$ adjustment applied for in vivo ${\mathrm{C}}_{\text{ss}}$ in EAD calculation. $\text{PPK}\_{\mathrm{f}}_{\mathrm{u}}\_\text{EF}$ is PPK model with EF applied for ${\text{ACC}}_{\text{ER}}$ and ${\mathrm{f}}_{\mathrm{u}}$ adjustment applied for in vivo ${\mathrm{C}}_{\text{ss}}$ in EAD calculation. ${\text{ACC}}_{\text{ER}}$, pseudo median activity concentration at cutoff from estrogen receptor pathway model; ${\text{CL}}_{\text{int}}$, intrinsic clearance ($\mathrm{L}/\mathrm{h}$); EAD, equivalent administered dose; EF, enrichment factor; ${\mathrm{f}}_{\mathrm{u}}$, fraction of chemical unbound to plasma protein; LEL, lowest effect level; QPPR, quantitative property-property relationship; QSAR, quantitative structure-activity relationship; PK, pharmacokinetic.