Figure 1.

Structures of models used for analyses. (A) The PPK model is a one-compartment model assuming 100% absorption and total clearance as the sum of hepatic and renal clearance. (B) The httk.3comp model (HT3C) includes compartments for gut lumen, gut, liver, and one compartment including all remaining tissues (figure adapted from Pearce et al. 2017). (C) The GP PBPK model consists of 14 tissue compartments as shown in the figure [figure adapted from the PBPK Model Editor window in the GastroPlus™ software (Simulations Plus, Inc.)]. To simulate absorption through the gastrointestinal tract, the model incorporates the ACAT model consisting of nine compartments (stomach, duodenum, jejunum 1, jejunum 2, ileum 1, ileum 2, ileum 3, caecum, and ascending colon). ACAT, advanced compartmental absorption and transit; ${\text{CL}}_{\text{Hepatic}}$, hepatic clearance ($\mathrm{L}/\mathrm{h}$); ${\text{CL}}_{\text{int}}$, intrinsic clearance ($\mathrm{L}/\mathrm{h}$); ${\text{CL}}_{\text{Renal}}$, renal clearance ($\mathrm{L}/\mathrm{h}$); ${\mathrm{C}}_{\text{ss}}$, steady state plasma concentration; ${\mathrm{f}}_{\mathrm{u}}$, fraction of chemical unbound to plasma protein; GFR, glomerular filtration rate ($\mathrm{L}/\mathrm{h}$); PBPK, physiologically based pharmacokinetic; PPK, one-compartment population-based pharmacokinetic model; ${\mathrm{Q}}_{\text{liver}}$, liver blood flow ($\mathrm{L}/\mathrm{h}$); Q, Tissue blood flow (mL/s); V, Tissue Volume (mL).