Fig 2: Comparison of simulated (red lines) and observed (black symbols and lines) GGF2-mediated hepatic responses. Solid red lines represent plasma ALT and total bilirubin simulation results in the SimCohorts (n = 16). Plasma total bilirubin simulation results in the baseline human with varying magnitudes of GGF2 effects on bilirubin transporters are also presented to account for to account for uncertainty around transcriptional data. ALT, alanine aminotransferase; TB, total bilirubin.

Fig 3: Sensitivity analysis of GGF2 effects on bilirubin and bile acid disposition-related mechanisms in the baseline human. Red and green arrows in the headers indicate down- or upregulation of the respective pathway based on transcriptional data [4]. The default toxicity parameter values across all panels are based on the magnitude of GGF2 impact on each individual mechanism using the transcriptional data and were subsequently decreased or increased as indicated in the color-coded legend. ALT, alanine aminotransferase; ATP, adenosine triphosphate; CDCA, chenodeoxycholic acid; CL, centrilobular; TB, total bilirubin.

Fig 4: In-vitro-like simulations of GGF2-mimicking LAMPS experiments. GastroPlus PBPK modeling of GGF2 was used to simulate steady-state plasma concentrations that match the dosing concentrations of GGF2 in the LAMPS experiments ((A): 10 ng/mL; (C): 100 ng/mL; (E): 382 ng/mL) to subsequently predict the corresponding hepatic interstitial concentrations. Hepatic interstitial concentrations were used to drive the mechanisms underlying altered bile acid secretion (B,D,F) parameterization in BIOLOGXsym. Red solid circles with error bars represent simulated values (mean ± SD) in BIOLOGXsym on days 4, 5 and 6, whereas solid black circles with error bars represent the LAMPS data (mean ± SD) on these days. GCDCA, glycochenodeoxycholic acid; TCA, taurocholic acid; BAs, bile acids.