Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation

Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation

Schadt H S; Wolf A; Mahl J A; Wuersch K; Couttet P; Schwald M; Fischer A; Lienard M; Emotte C; Teng C H; Skuba E; Richardson T A; Manenti L; Weiss A; Porta D G; Fairhurst R A; Kullak-Ublick G A; Chibout S D; Pognan F; Kluwe W; Kinyamu-Akunda J

Toxicological Sciences

2018

2018-05

The FGF19- fibroblast growth factor receptor (FGFR4)-beta Klotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1., elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels.

7alpha-hydroxy-4-cholesten-3-one; aminotransferase; aspartate-aminotransferase isozymes; bile acids; Cyp7a1; FGF19; fibroblast-growth-factor; fibroblast-growth-factor; hepatocellular carcinoma; identification; induced liver-injury; Klotho beta; lipophilicity; liver injury; mitigation; nuclear receptor; serum; sinusoidal endothelial-cells; suppression; tgr5; Toxicology

Journal Article

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

265-278

1

163