DILIsym has been described previously (Bhattacharya et al., 2012 (link); Shoda et al., 2014 (link); Woodhead et al., 2012 (link)). Briefly, DILIsym is a multi-scale and “middle-out” platform focused on the liver as the primary organ of interest, which includes detailed liver cellular dynamics and biochemistry, extends to whole body drug distribution and systemic circulation of mediators and biomarkers, and accounts for inter-individual differences through variation in anthropometrics and biochemistry. Essential processes occur in interacting sub-models: physiologically based pharmacokinetics (PBPK), bile acid transporter inhibition, mitochondrial dysfunction, oxidative stress, hepatocyte life cycle, and macrophage and endothelial cell life cycles. Parameter values are informed by experimental data, with sub-model and system-level behaviors optimized for consistency with exemplar compounds (Howell et al., 2012 (link); Woodhead et al., 2014 (link), 2012 (link)). Parameter solutions include those consistent with human, rat, and mouse data (Woodhead et al., 2012 (link), 2014 (link)). Generally, simulations for the current study were conducted in the baseline simulated human, and in simulated populations (SimPops) as described previously (Longo et al., 2016 (link); Yang et al., 2015 (link)); tolvaptan-specific adjustments are described in detail below.