Indications
Fezolinetant is prescribed for the management of moderate to severe vasomotor symptoms associated with menopause. These symptoms, commonly experienced by menopausal women, can significantly impact quality of life, and fezolinetant offers a therapeutic option for alleviation.
Pharmacodynamics
Fezolinetant exhibits a high affinity for the neurokinin 3 (NK3) receptor, with a Ki value ranging from 19.9 to 22.1 nmol/L. This binding affinity is over 450 times more potent than its affinity for the NK1 or NK2 receptors. Clinical studies have shown that treatment with fezolinetant does not significantly alter levels of sex hormones such as follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate in menopausal women. Notably, a temporary reduction in luteinizing hormone (LH) levels was noted at peak concentrations. Importantly, even at doses 20 times the maximum recommended dose, fezolinetant does not induce a clinically significant prolongation of the QT interval. In phase 2a clinical trials, a dosage of 90 mg twice daily resulted in more than a 50% reduction in the frequency and severity of vasomotor symptoms in postmenopausal women, with improvements observed within the first week and sustained throughout the 12-week treatment period.
Absorption
In healthy women, fezolinetant's maximum concentration (Cmax) and area under the curve (AUC) increase proportionally over a dosage range of 20 to 60 mg once daily, equating to 0.44 to 1.33 times the approved recommended dose. Steady-state plasma concentrations are typically achieved after two doses, administered once daily, with minimal accumulation. The median time to reach Cmax in healthy women is 1.5 hours, with a range of 1 to 4 hours.
Metabolism
Fezolinetant undergoes primary metabolism through the CYP1A2 enzyme, with lesser contributions from CYP2C9 and CYP2C19 enzymes. The main metabolite identified in plasma is ES259564, which exhibits approximately 20-fold less potency than the parent compound. The ratio of metabolite to parent compound ranges from 0.7 to 1.8, indicating significant metabolic conversion upon administration.
Mechanism of Action
Fezolinetant functions as a neurokinin 3 (NK3) receptor antagonist, specifically targeting the neurokinin B (NKB) receptors located on the kisspeptin/neurokinin B/dynorphin (KNDy) neurons. This action inhibits the binding of neurokinin B, thereby modulating neuronal activity within the thermoregulatory center.
