Fezolinetant

Fezolinetant is a non-hormonal selective neurokinin 3 (NK3) receptor antagonist. It blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron, which is postulated to restore the balance in KNDy neuronal activity in the thermoregulatory centre of the hypothalamus.

In postmenopausal women, with fezolinetant treatment, a transient decrease of luteinizing hormone (LH) levels was observed. No clear trends or clinically relevant changes in sex hormones measured (follicle-stimulating hormone (FSH), testosterone, oestrogen, and dehydroepiandrosterone sulphate) in postmenopausal women were observed.

In healthy women, fezolinetant C_max and AUC increased proportionally with doses between 20 and 60 mg once daily.

After once-a-day dosing, steady-state plasma concentrations of fezolinetant were generally reached by day 2, with minimal fezolinetant accumulation. The pharmacokinetics of fezolinetant do not change over time.

Absorption

Fezolinetant C_max is usually achieved at 1 to 4 hours post-dose. No clinically significant differences in fezolinetant pharmacokinetics were observed following administration with a high-calorie, high-fat meal. Fezolinetant may be administered with or without food.

Distribution

The mean apparent volume of distribution (V_z/F) of fezolinetant is 189 l. The plasma protein binding of fezolinetant is low (51%). The distribution of fezolinetant into red blood cells is almost equal to plasma.

Biotransformation

Fezolinetant is primarily metabolised by CYP1A2 to yield oxidised major metabolite ES259564. ES259564 is approximately 20-fold less potent against human NK3 receptor. The metabolite-to-parent ratio ranges from 0.7 to 1.8.

Elimination

The apparent clearance at steady-state of fezolinetant is 10.8 l/h. Following oral administration, fezolinetant is mainly eliminated in urine (76.9%) and to a lesser extent in faeces (14.7%). In urine, a mean of 1.1% of the administered fezolinetant dose was excreted unchanged and 61.7% of the administered dose was excreted as ES259564. The effective half-life (t_1/2) of fezolinetant is 9.6 hours in women with VMS.

Special populations

Effects of age, race, body weight, and menopause status

There are no clinically relevant effects on age (18 to 65 years), race (Black, Asian, Other), body weight (42 to 126 kg), or menopause status (pre-, post-menopause) on the pharmacokinetics of fezolinetant.

Hepatic impairment

Following single-dose administration of 30 mg fezolinetant in women with Child-Pugh Class A (mild) chronic hepatic impairment, mean fezolinetant C_max increased by 1.2-fold and AUC_inf increased by 1.6- fold, relative to women with normal hepatic function. In women with Child-Pugh Class B (moderate) chronic hepatic impairment, mean fezolinetant C_max decreased by 15% and AUC_inf increased by 2-fold. The C_max of ES259564 decreased in both mild and moderate chronic hepatic impairment groups while AUC_inf and AUC_last slightly increased less than 1.2-fold.

Fezolinetant has not been studied in individuals with Child-Pugh Class C (severe) chronic hepatic impairment.

Renal impairment

Following single-dose administration of 30 mg fezolinetant, there was no clinically relevant effect on fezolinetant exposure (C_max and AUC) in women with mild (eGFR 60 to less than 90 ml/min/1.73 m²) to severe (eGFR less than 30 ml/min/1.73 m²) renal impairment. The AUC of ES259564 was not changed in women with mild renal impairment but increased approximately 1.7- to 4.8-fold in moderate (eGFR 30 to less than 60 ml/min/1.73 m²) and severe renal impairment. Fezolinetant is not recommended for use in women with severe renal impairment or with end-stage renal disease because of lack of long-term safety data in this population.

Fezolinetant has not been studied in individuals with end-stage renal disease (eGFR less than 15 ml/min/1.73 m²).

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Repeated dose toxicity

Repeated administration of fezolinetant to rats and monkeys showed the effects consistent with the primary pharmacological action (oestrous cycle disruptions, the lack of ovarian activity, decreased uterine and/or ovarian weight, uterine atrophy). These effects were observed at high exposure levels (>10-fold of the anticipated clinical exposure at the human therapeutic dose of 45 mg). Furthermore, in rats, secondary effects were seen on the liver and thyroid which are considered to be an adaptive response to the enzyme induction and in the absence of functional impairment and accompanying necrotic changes were considered non-adverse. The finding of thyroid follicular cell hyperplasia is considered secondary to the liver enzyme induction due to the increased thyroid hormone metabolism, resulting in the positive feedback to the pituitary for the stimulation of thyroid stimulating hormone production and increased thyroid activity. It is generally accepted that rodents are more sensitive to this type of liver-mediated thyroid toxicity than humans, thus these findings are not expected to be clinically relevant.

In monkeys, thrombocytopenia, sometimes associated with haemorrhagic episodes and regenerative anaemia, was seen following repeated administration at high dose levels (>60-fold of human exposure at the human therapeutic dose).

Genotoxicity

Fezolinetant and its major metabolite ES259564 showed no genotoxic potential in the in vitro bacterial reverse mutation test, in vitro chromosomal aberration test, and in vivo micronucleus test.

Carcinogenicity

An increase in the incidence of thyroid follicular cell adenoma was noted in a 2-year rat carcinogenicity study (186-fold of human exposure at the human therapeutic dose). The increase is considered to be a rat specific effect secondary to the induction of hepatocyte metabolic enzymes and does not constitute a clinical carcinogenic risk.

Additionally, increased incidence of thymomas, which slightly exceeded the historical control range, was observed in both species. However, these findings were only noted at exposure levels significantly in excess (>50-fold) of the clinical exposure at the human therapeutic dose, and therefore are not expected to be relevant to humans.

Reproductive and developmental toxicity

Fezolinetant had no effect on female fertility or early embryonic development in the rat study at exposure levels of 143-fold of human exposure at the human therapeutic dose.

In embryo-foetal development toxicity studies, embryo-lethality was noted at the exposure levels of 128- and 174-fold at the human therapeutic dose in rats and rabbits, respectively. Rabbits also showed increased late resorption and reduced foetal weight at the exposure levels of 28-fold at the human therapeutic dose. Fezolinetant did not show teratogenic potential in either rats or rabbits. In the preand post-natal development study in rats, increased dose-responsive total litter loss/abortions was observed at the exposure levels of 36-fold of the anticipated clinical exposure at the maximum recommended human dose, while reduced sexual maturation in male progeny was seen at the 204-fold exposure levels at the maximum recommended human dose.

Following administration of radiolabelled fezolinetant to lactating rats, the radioactivity concentration in milk was higher than that in the plasma at all time points, indicating excretion of fezolinetant and/or its metabolites in the breast milk.

Environmental risk assessment

Environmental risk assessment studies have shown that fezolinetant may pose a risk to the aquatic environment.