| Autor: |
Longo DM; DILIsym Services, Inc., Research Triangle Park, North Carolina 27709., Woodhead JL; DILIsym Services, Inc., Research Triangle Park, North Carolina 27709., Walker P; Cyprotex, Inc., Macclesfield SK10 4TG, UK., Herédi-Szabó K; SOLVO Biotechnology, Szeged 6728, Hungary., Mogyorósi K; SOLVO Biotechnology, Szeged 6728, Hungary., Wolenski FS; Takeda Pharmaceuticals International, Inc., Cambridge, Massachusetts 02139., Dragan YP; Takeda Pharmaceuticals International, Inc., Cambridge, Massachusetts 02139., Mosedale M; UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.; UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709., Siler SQ; DILIsym Services, Inc., Research Triangle Park, North Carolina 27709., Watkins PB; DILIsym Services, Inc., Research Triangle Park, North Carolina 27709.; UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.; UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709., Howell BA; DILIsym Services, Inc., Research Triangle Park, North Carolina 27709. |
| Abstrakt: |
TAK-875 (fasiglifam), a GPR40 agonist in development for the treatment of type 2 diabetes (T2D), was voluntarily terminated in Phase III trials due to adverse liver effects. The potential mechanisms of TAK-875 toxicity were explored by combining in vitro experiments with quantitative systems toxicology (QST) using DILIsym, a mathematical representation of drug-induced liver injury. In vitro assays revealed that bile acid transporters were inhibited by both TAK-875 and its metabolite, TAK-875-Glu. Experimental data indicated that human bile salt export pump (BSEP) inhibition by TAK-875 was mixed whereas sodium taurocholate co-transporting polypeptide (NTCP) inhibition by TAK-875 was competitive. Furthermore, experimental data demonstrated that both TAK-875 and TAK-875-Glu inhibit mitochondrial electron transport chain (ETC) enzymes. These mechanistic data were combined with a physiologically based pharmacokinetic (PBPK) model constructed within DILIsym to estimate liver exposure of TAK-875 and TAK-875-Glu. In a simulated population (SimPops) constructed to reflect T2D patients, 16/245 (6.5%) simulated individuals developed alanine aminotransferase (ALT) elevations, an incidence similar to that observed with 200 mg daily dosing in clinical trials. Determining the mode of bile acid transporter inhibition (Ki) was critical to accurate predictions. In addition, simulations conducted on a sensitive subset of individuals (SimCohorts) revealed that when either BSEP or ETC inhibition was inactive, ALT elevations were not predicted to occur, suggesting that the two mechanisms operate synergistically to produce the observed clinical response. These results demonstrate how utilizing QST methods to interpret in vitro experimental results can lead to an improved understanding of the clinically relevant mechanisms underlying drug-induced toxicity. |
