Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

Abstract

Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

“…But most interestingly, only TAK875‐GlucA 4 became a very potent inhibitor of MRP2, which is very likely a competitive inhibition as a substrate of this transporter. While the inhibitory potential of TAK875 towards most transporters is very similar between three former publications the results regarding MRP2 are contradictory. While Lie et al and Otieno et al describe a potent inhibition, the publication of Wolenski et al describes a simulation of MRP2, a tendency that was also observed by us.…”

“…While the inhibitory potential of TAK875 towards most transporters is very similar between three former publications the results regarding MRP2 are contradictory. While Lie et al and Otieno et al describe a potent inhibition, the publication of Wolenski et al describes a simulation of MRP2, a tendency that was also observed by us. Further scientific analysis of such a striking difference in results is regarded as very meaningful, as inhibition of efflux transporters of the MRP family is highly discussed as a mechanism of hepatotoxicity.…”

“…Although these qualities are generally thought to result in less sensitivity to drug‐induced mitochondrial dysfunction in HepG2 cells we may hypothesize that the different metabolic capabilities of primary hepatocytes compared with HepG2 cells may be the basis for the differences in bioenergetic response to TAK875 1 observed. Wolenski et al described no cytotoxic effect at concentrations ≤25 µM after 24‐hour treatment, no effects on respiratory function at concentrations ≤ 20 µM, no GSH depletion with TAK875 1 and TAK875‐GlcA 4, respectively, in primary human hepatocytes. In addition, no shift in energy production via OXPOS to glycolysis in human HepG2 cells could be determined to demonstrate a ratio of less than 2 for EC 50 ‐ATPglu/EC 50 ‐ATPgal .…”

“…In addition to earlier studies, our experiments indicate that there is a significant mechanistic contribution to the hepatotoxic effects observed with fasiglifam, which is particularly driven by one of the glucuronide metabolites (TAK875‐M1‐GlcA 8 ). Conjugation to TAK875‐GlcA 4 was shown to be the primary elimination pathway of TAK875 1 in preclinical species, such as rats, dogs, and also humans . We investigated the in silico toxicity profile as well as the in vitro cytotoxicity, reactivity, and transporter characteristics of TAK875 1 and the related metabolites as potential mechanism for liver toxicity.…”

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

“…DILIsym ® modeling has been conducted with other, more potent BSEP inhibitors recently like AMG 009 and TAK‐875 . However, in neither case has elevated total and/or fractionated bile acids been reported in these individual clinical cases of hepatotoxicity due, most likely to lack of clinical samples to examine these effects, even though this phenomenon has been demonstrated in nonclinical species treated with the same drug …”