Pharmacokinetics and Safety of Fezolinetant in Women with Hepatic or Renal Impairment.

Abstract

The neurokinin 3 receptor antagonist fezolinetant is an approved treatment for vasomotor symptoms due to menopause. The impacts of hepatic and renal impairment on the pharmacokinetics and safety of a single oral dose of fezolinetant 30 mg were investigated in two independent studies. The studies enrolled healthy women and women with mild or moderate hepatic impairment (defined by Child-Pugh classification) or mild to severe renal impairment (categorized by estimated glomerular filtration rate). Blood samples for fezolinetant and its metabolite, ES259564, were collected predose and up to 96 h postdose. Safety was assessed using treatment-emergent adverse events (TEAEs). Overall, 26 and 27 women were enrolled in the hepatic and renal studies. Fezolinetant exposure (area under the concentration-time curve from time of dosing to infinity [AUC_inf]) was higher in those with hepatic impairment than women with normal function (geometric mean ratios [90% confidence interval]: mild/healthy control: 155.89% [108.04%-224.92%], moderate/healthy control: 196.11% [131.64%-292.15%]). The AUC_inf results for ES259564 were similar between women who were hepatically impaired and of normal functioning. Renal impairment did not substantially increase the exposure of fezolinetant. However, those with moderate or severe renal impairment had higher AUC_last (from time of dosing to last measurable concentration) results for ES259564 than healthy women (moderate/healthy control: 177.14 [120.02-261.44], severe/healthy control: 478.56 [347.93-658.22]). No serious TEAEs were reported in either study. In conclusion, hepatic impairment affects the metabolism of fezolinetant as shown by progressive increases in systemic exposure. Marginal impacts were noted in women with renal impairment.