Concentration–QTc Modeling to Support Clinical Development of Fezolinetant

Abstract Fezolinetant is a non‐hormonal, selective neurokinin‐3 receptor antagonist that blocks neurokinin B activation of kisspeptin/neurokinin B/dynorphin neurons to thereby modulate neuronal activity in the thermoregulatory center. Fezolinetant has been approved in many regions, including North America, Europe, Asia, and Australia for the treatment of vasomotor symptoms associated with menopause at a dose of 45 mg once daily (QD). The risk of potential QT prolongation for fezolinetant was assessed prior to the initiation of the phase 3 trials. A concentration–QTc (C–QTc) analysis was performed in accordance with recommendations from ICH E14 Guideline and utilized data from a phase 1 single and multiple ascending dose study, which tested single doses up to 900 mg and multiple daily doses up to 720 mg in healthy male and female participants. The fezolinetant C–QTc relationship indicated no clinically relevant QT prolongation at therapeutic or supra‐therapeutic doses of fezolinetant. Based on these modeling results as well as data from other clinical and non‐clinical studies, no thorough QT/QTc (TQT) study was required for fezolinetant.