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

Abstract

The FGF19- fibroblast growth factor receptor (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, 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.

• Authors: Heiko S Schadt, Armin Wolf, Joerg Andreas Mahl, Kuno Wuersch, Philippe Couttet, Marianne Schwald, Audrey Fischer, Mathilde Lienard, Corinne Emotte, Chi-Hse Teng, Elizabeth Skuba, Terrilyn A Richardson, Luigi Manenti, Andreas Weiss, Diana Graus Porta, Robin A Fairhurst, Gerd A Kullak-Ublick, Salah-Dine Chibout, Francois Pognan, William Kluwe, Jacqueline Kinyamu-Akunda
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 163 Issue 1 Pg. 265-278 (05 01 2018) ISSN: 1096-0929 [Electronic] United States
• PMID: 29432567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bile Acids and Salts
• Piperazines
• Protein Kinase Inhibitors
• Pyridines
• Cholestyramine Resin
• Alanine Transaminase
• Receptor, Fibroblast Growth Factor, Type 4
• roblitinib

Topics

• Alanine Transaminase (biosynthesis, blood)
• Animals
• Bile Acids and Salts (biosynthesis, blood)
• Cholestyramine Resin (pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Female
• Liver (drug effects, enzymology)
• Male
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (blood, toxicity)
• Pyridines (pharmacology)
• Receptor, Fibroblast Growth Factor, Type 4 (antagonists & inhibitors)
• Toxicity Tests
• Toxicokinetics