Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Bile acid sequestration by cholestyramine mitigates FGFR4 inhibition-induced ALT elevation

Schadt, Heiko and Wolf, Armin and Mahl, Joerg Andreas and Wuersch, Kuno and Couttet, Philippe and Schwald, Marianne and Fischer, Audrey and Lienard, Mathilde and Emotte, Corinne and Teng, Chi-Hse and Skuba, Elizabeth and Richardson, Terrilyn and Manenti, Luigi and Weiss, Andreas and Graus Porta, Diana and Fairhurst, Robin and Kullak-Ublick, Gerd and Chibout, Salah-Dine and Pognan, Francois and Kluwe, William and Kinyamu-Akunda, Jacqueline (2018) Bile acid sequestration by cholestyramine mitigates FGFR4 inhibition-induced ALT elevation. Toxicological Sciences. ISSN 1096-60801096-0929

Abstract

The FGF19-FGFR4-βKlotho (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 (HCC), establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for HCC, currently in Phase I/II clinical studies. In preclinical studies in mice and dogs, single or repeated doses of FGF401 led to induction of Cyp7a1 in the liver, the rate-limiting enzyme in BA biosynthesis, and elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one (C4). As a consequence the BA pool size increased, serum cholesterol decreased, and diarrhea occurred in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in mice and dogs 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 co-administration of the BA sequestrant cholestyramine (CHO) to test this hypothesis. Here we show that co-administration of CHO with FGF401 prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. BA profile analysis revealed that effects of BA sequestration were most pronounced for secondary BAs of high hydrophobicity. Indeed, correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid (TLCA) and taurodeoxycholic acid (TDCA), the major secondary BAs in dog plasma, making a mechanistic link between ALT elevation and changes in BA pool hydrophobicity plausible. These data therefore confirm our hypothesis that the increase in ALT with FGF401 is likely secondary to BAs increases and can be prevented by CHO. In human subjects, CHO may offer the potential to mitigate elevations in serum aminotransferases that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels, in addition to its established role in diarrhea management.

Item Type: Article
Keywords: FGF401, FGFR4, fibroblast growth factor, fibroblast growth factor receptor, FGF19, FGF15, Klotho beta, hepatocellular carcinoma, HCC, Cyp7a1, C4, 7alpha-hydroxy-4-cholesten-3-one, bile acid, alanine aminotransferase, alanine transferase, aspartate aminotransferase, aspartate transferase, ALT, AST, bile acid sequestrant, cholestyramine, mitigation, kupffer cell, liver
Date Deposited: 17 Apr 2018 00:45
Last Modified: 17 Apr 2018 00:45
URI: https://oak.novartis.com/id/eprint/35335

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.