What are the drug interactions with fezolinetant?

Published

Fezolinetant is contraindicated in individuals using CYP1A2 inhibitors. Fezolinetant is a substrate of CYP1A2 and concomitant use with drugs that are weak, moderate, or strong CYP1A2 inhibitors increases the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of fezolinetant

  • Based on in vitro and in vivo data, fezolinetant is not expected to affect the pharmacokinetics of drugs that are substrates of CYP isoenzymes or drug transporters.1
  • Several electronic drug databases describe theoretical drug-drug interactions based upon each drug’s metabolism (e.g., Epocrates®, Micromedex®, UpToDate® Lexidrug™, Drugs.com).2–5 

  • Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19.6 A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8.

Clinical studies and model-informed approaches6

  • Strong CYP1A2 Inhibitors: Fezolinetant maximum plasma concentration (Cmax) increased by 80% and area under the concentration-time curve (AUC) increased by 840% following concomitant use with fluvoxamine.
  • Moderate CYP1A2 Inhibitors: Fezolinetant Cmax increased by 40% and AUC increased by 360% following concomitant use with mexiletine 400 mg every 8 hours. 
  • Weak CYP1A2 Inhibitors: Fezolinetant Cmax increased by 30% and AUC increased by 100% following concomitant use with cimetidine 300 mg every 6 hours. 
  • No clinically significant differences in fezolinetant exposure were observed in smokers (moderate CYP1A2 inducer).

In vitro studies6

  • Fezolinetant and ES259564 are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fezolinetant and ES259564 are not inducers of CYP1A2, CYP2B6, and CYP3A4.

Transporter systems6

  • Fezolinetant is not a substrate nor an inhibitor of P-glycoprotein (P-gp). ES259564 is a substrate of P-gp, but not an inhibitor of P-gp.
  • Both fezolinetant and ES259564 are not substrates of BCRP, OATP1B1, and OATP1B3. In addition, ES259564 is not a substrate of OAT1, OAT3, OCT2, MATE1, and MATE2-K.

  1. Data on file.

  2. Epocrates®. CYP450 Enzyme and P-gp Transporter Inhibitor Check. Available at: https://www.epocrates.com/.

  3. UpToDate® LexiDrugTM. Interactions. Available at: https://online.lexi.com.

  4. Drugs.com®. Interaction Checker. Available at: https://www.drugs.com.

  5. Micromedex® Pharmaceutical Knowledge. Available at: https://www.micromedexsolutions.com

  6. VEOZAH [package insert]. Northbrook, IL, USA: Astellas Pharma, Inc. Available at: https://www.astellas.com/us/system/files/veozah_uspi.pdf.

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