Systems Pharmacology and DILI

The DILIsym systems pharmacology approach has been applied to clinical development in multiple ways. DILIsym simulations were able to predict the species differences between rats and humans with respect to liver injury following the administration of troglitazone (Yang et al., 2014) and methapyrilene (Howell et al., 2012). Employing in vitro and 

drugs that cause an increase in hepatic SEA, such as FAO inhibitors or VLDL release inhibitors, can now be evaluated for DILI risk with DILIsym. 

DILIsym was recently applied to evaluate each of these hypotheses with the simulation of 80 mg q.d. etomoxir dosing in a simulated population (SimPops )- The FAO inhibition effects were based on in vitro data (Agius et al., 1991). In simulations where the model parameters excluded contributions of lipotoxicity to liver injury, no simulated patients were predicted to have ALT increases. However, simulations including lipotoxicity showed an incidence of DILI that was similar to that seen in the ERGO trial, with 2/300 simulated patients predicted to have ALT 5x ULN (see Table 8.2). 

Moreover, the predicted ALT increases did not occur until after 4-6 weeks of dosing, as was observed in the ERGO trial. It is reasonable to conclude from the comparison of the DILIsym simulation results with the clinical data that etomoxir caused an accumulation of lipids due to the FAO inhibition properties of the compound and lipotoxicity for the LFTs in the ERGO trial. 

Assimilating a comprehensive approach for dealing with DILI during the drug discovery and development process is a daunting task. As one can see from the numerous 

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