What are the possible mechanisms of hepatotoxicity for fezolinetant?

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DILIsym® modeling indicated a dose-dependent relationship between fezolinetant exposure and hepatotoxicity, mainly caused by electron transport chain inhibition

  • Nine participants in the phase 2b dose-ranging study (n = 352) experienced transient, asymptomatic elevations in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceeding three times the upper limit of normal (> 3x ULN).1
  • DILIsym®, a quantitative systems toxicology model of drug-induced liver injury (DILI), was used to help predict this potential risk with various doses of fezolinetant prior to Phase 3 trials.1 
  • The DILIsym® platform used in vitro experimental data of potential mechanisms of drug-intrinsic toxicity and physiologically based pharmacokinetic model-derived estimates of fezolinetant and its major metabolite (ES259564) liver exposure to predict DILI.

  • No ALT elevations > 3x ULN were predicted for simulations performed at therapeutic doses for the virtual healthy volunteers simulated population. Mild increases in ALT elevation frequency above placebo were observed for simulations performed at therapeutic doses for the virtual metabolic syndrome-associated fatty liver disease (MAFLD) population and included a Hy’s law case at 45 and 60 mg once daily. Simulations in the MAFLD cohort with the sub-model of mitochondrial biogenesis influence mitigated the predicted Hy’s law case.
  • Efficacy and acceptable liver safety of fezolinetant 30 and 45 mg once daily were subsequently confirmed in Phase 3 trials, leading to drug approval of 45 mg once daily.1 

  1. Nielsen JC, Woodhead JL, Howell BA, et al. Quantitative Systems Toxicology Modeling with DILIsym to Support Phase 3 Dose Selection for Fezolinetant. Clin. Pharmacol. Ther. 2026; Available at: https://doi.org/10.1002/cpt.70194.

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