Inhibition of UDP-glucuronosyltransferases by fedratinib, implying a high risk of drug-drug interactions

Fedratinib is the second drug approved by the FDA for adult patients with myelofibrosis (MF) following ruxolitinib; however, the mechanism of its dose-limiting toxicity, particularly hepatotoxicity, remains poorly unclear. Given that inhibition of UDP-glucuronosyltransferases (UGTs) is a key predictor of drug-induced liver injury, this research investigates the inhibition of fedratinib on UGTs and human liver microsomes (HLMs), and evaluates the associated risks of adverse drug reactions. Our screening revealed that fedratinib potently inhibit UGT1A1, UGT1A3, and UGT2B15. Enzyme kinetic analyses further indicated that fedratinib exhibited competitive inhibition for UGT1A1-mediated 4-methylumbelliferone (4-MU) glucuronidation ( K i,u  = 0.39 ± 0.03 μM), and UGT1A3-mediated 4-MU glucuronidation ( K i,u  = 0.61 ± 0.18 μM). In HLMs, it exhibited mixed inhibition of SN-38 glucuronidation ( K i,u  = 0.58 ± 0.13 μM) and non-competitive inhibition of chenodeoxycholic acid glucuronidation ( K i,u  = 2.38 ± 0.17 μM). The results of risk assessment indicated that clinically relevant doses of fedratinib could significantly increase the area under curve (AUC) of drugs mainly metabolized by UGT1A1 and UGT1A3, suggesting a potential risk of clinically significant drug-drug interactions (DDIs). The current research provides useful information for the possible hepatotoxicity mechanism and clinical safe medication of fedratinib.