TAK-875 (fasiglifam), a GPR40 agonist in development for treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. Alanine aminotransferase elevations were observed in approximately 2% of TAK-875 treated subjects. The potential mechanisms of TAK-875 toxicity were explored using in vitro experiments and quantitative systems toxicology (QST) analysis using DILIsym® , a mathematical model of drug-induced liver injury. In vitro assays revealed that human Bile Salt Export Protein (BSEP) was inhibited by both TAK-875 (Ki = 17.2 uM) and TAK-875-Glu (IC50 = 41.6 uM). The mode of BSEP inhibition by TAK-875 was found to be mixed with alpha = 2.172. Furthermore, in vitro assays demonstrated that both TAK-875 and TAK-875-Glu inhibit the mitochondrial electron transport chain (ETC). These mechanistic data were combined with a physiologically-based pharmacokinetic (PBPK) model constructed within DILIsym® used to estimate liver exposure of TAK-875 and TAK-875-Glu. 17 out of 245 (6.91%) individuals in a simulated population (SimPopsTM) constructed to reflect Type 2 diabetes patients developed ALT elevations. This generally recapitulates, though mildly overpredicts, the actual toxicity. In addition, simulations conducted on a sensitive sub-population of individuals (SimCohortsTM) revealed that when either BSEP inhibition or ETC inhibition was removed from the simulation, ALT elevations did not occur. This suggests that both BSEP inhibition and ETC inhibition are necessary to explain
the observed toxicity, and in this model the two mechanisms operate synergistically to produce the observed clinical response. These results demonstrate how combining in vitro experimental methods with QST methods can lead to improved predictions about the underlying mechanisms behind drug-induced toxicity than either method can provide alone.
Society of Toxicology 56th Annual Meeting & ToxExpo, March 13-15, 2017, Baltimore, MD
By Jeffery Woodhead, Scott Q Siler, Paul B Watkins, Brett A Howell