Chemical formula: C₃₃H₃₅F₇N₄O₃ Molecular mass: 668.26 g/mol PubChem compound: 16063568
Elinzanetant is a non-hormonal, selective neurokinin 1 (NK-1) and 3 (NK-3) receptors antagonist. It blocks NK-1 and NK-3 receptors signalling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which is postulated to normalise neuronal activity involved in thermo- and sleep regulation.
No clinically relevant prolongation of the QTc interval was observed after single oral administration of elinzanetant at doses up to 5 times the maximum recommended dose.
In healthy premenopausal women having received elinzanetant over 21 days, results showed changes of plasma concentrations of sexual hormones (i.e. dose-related reductions of LH, oestradiol, and progesterone) and prolongation of the menstrual cycle. Changes in female sex hormones that were observed, are consistent with the anticipated pharmacological effects of elinzanetant on hypothalamic kisspeptin/neurokinin B/dynorphin neurons.
In postmenopausal women treated with elinzanetant, a transient decrease in luteinizing hormone (LH) levels was observed. No significant changes were noted in oestrogen, follicle-stimulating hormone (FSH), and testosterone levels in this population. These effects are not clinically relevant.
Elinzanetant soft gel capsules show a dose-proportional increase in Cmax in the dose range 25 mg to 600 mg. The AUC increases dose-proportional in the dose range 25 mg to 120 mg and greater than dose proportional in the dose range 160 mg to 600 mg.
Steady state plasma concentrations of elinzanetant were reached 5–7 days after daily dosing, with <2-fold accumulation.
The absolute bioavailability of elinzanetant is 52%.
Administering 120 mg elinzanetant with food reduces Cmax with 60-70% and the AUC(0-24) with 20-40%, but no effect on the AUC was observed. The tmax shifted from 1-1.5 hours under fasted conditions to 3-4 hours under fed conditions. The food effect is not expected to be of clinical relevance for efficacy. Elinzanetant may be administered with or without food.
The plasma protein binding of elinzanetant is high (>99%) and is affected by circadian fluctuation. The blood-to-plasma ratio is between 0.6 and 0.7. The mean volume of distribution after intravenous administration at steady state (Vss) of elinzanetant is 137 L, indicating extensive extravascular distribution. Exposure of elinzanetant in human brain was shown by clinical positron emission tomography (PET) studies.
Elinzanetant is primarily metabolised by CYP3A4 to yield 3 active metabolites (M30/34 [13.7%], M27 [7.6%], M18/21 [4.9%]). Elinzanetant is also metabolised to a minor extend by CYP3A5 and UGTs. The active metabolites have similar potency for the human NK-1 and NK-3 receptors as compared to elinzanetant and contribute for <50% to the pharmacological effect. The ratio of these metabolites to parent in plasma is approximately 0.39.
Elinzanetant is mainly eliminated by metabolism. The clearance of elinzanetant after single intravenous dose is 8.77 L/h. Following oral administration of elinzanetant, approximately 90% of the dose was excreted with faeces (mainly as metabolites) and less than 1% with urine. The half-life of elinzanetant is approximately 45 hours in women with VMS after multiple dose and 11.2 to 33.8 hours in healthy volunteers after single dose.
Elinzanetant is in vitro a substrate for the P-glycoprotein (P-gp) transporter protein. No clinically relevant interaction with P-gp inhibitors and inducers is expected due to high permeability of elinzanetant through membranes and its main elimination through metabolism.
In a clinical pharmacokinetic study, following multiple-dose administration of 120 mg elinzanetant in patients with Child-Pugh Class A (mild) chronic hepatic impairment, mean elinzanetant Cmax increased by 1.2-fold and AUC(0-24) increased by 1.5-fold, relative to healthy volunteers with normal hepatic function. In patients with Child-Pugh Class B (moderate) chronic hepatic impairment, mean elinzanetant Cmax and AUC(0-24) increased by 2.3-fold.
Elinzanetant has not been studied in patients with Child-Pugh Class C (severe) chronic hepatic impairment.
In a clinical pharmacokinetic study, following single-dose administration of 120 mg elinzanetant in patients with moderate (eGFR 30-59 mL/min/1.73 m²) renal impairment, mean elinzanetant Cmax, unbound increased by 2.3-fold and AUCunbound increased by 2.2-fold. In patients with severe (eGFR less than 30 mL/min/1.73 m²) renal impairment, mean elinzanetant Cmax, unbound and AUCunbound increased by 1.9-fold.
Elinzanetant has not been studied in patients with end-stage renal disease (eGFR <15 mL/min/1.73 m²).
There are no clinically relevant effects on age (22 to 75 years), race (White, Black or African American, Asian), and body weight (45 to 129 kg) on the pharmacokinetics of elinzanetant.
In vitro studies indicated that at maximal intestinal concentrations elinzanetant is an inhibitor of CYP3A4 and the transporters P-glycoprotein (P-gp) and BCRP. At maximal portal vein concentrations, elinzanetant is an inhibitor of OATP1B1 and 1B3. At maximal systemic concentrations, elinzanetant is a direct and time-dependent inhibitor of CYP3A4 and an inhibitor of the transporters P-gp, BCRP, OATP1B3, and MATE1. Elinzanetant is not an inducer via AhR, CAR, or PXR at clinically relevant concentrations.
Clinical studies were performed investigating the inhibition potential of elinzanetant towards CYP3A4 (single and repeated dosing with elinzanetant) and the transporters P-gp (dabigatran etexilate) and BCRP, OATP1B1 and 1B3 (rosuvastatin). Elinzanetant is a weak inhibitor of CYP3A4 using midazolam as index substrate (Cmax increased 1.1- to 1.5-fold and AUC increased 1.4- to 1.8-fold). Elinzanetant did not affect the PK of dabigatran etexilate which was used as reference substrate of P-gp. Elinzanetant increased the PK of rosuvastatin (substrate of BCRP, OATP1B1 and 1B3) 1.2- to 1.3-fold.
No dedicated clinical DDI study was conducted towards MATE1. However, no effect on creatinine clearance was observed in a clinical study at supratherapeutic dosages of 600 mg. Overall, this indicates that the observed in vitro interaction potential is clinically not relevant.
In study OASIS 4, sparse blood samples were collected and concentrations of tamoxifen and its metabolites (N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen) were investigated. No effect on the steady state plasma concentrations of tamoxifen and its metabolites were observed when co-administered with elinzanetant.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, phototoxicity, genotoxicity and abuse potential.
Repeated dose toxicity studies were conducted in rats and cynomolgus monkeys. In female rats, daily administration of elinzanetant for 4 weeks at doses representing 40-fold the AUC(0-24) at the human therapeutic dose showed mucification of the vaginal epithelium, uterine atrophy, and persistent corpora lutea.
In a single 13-week study in rats with twice daily dosing, daily administration of elinzanetant at doses representing 4-fold (males) or 7-fold (females) the AUC(0-24) at the human therapeutic dose led to involuntary muscle contractions from day 24 in 10/88 animals, which later had also convulsions from day 34. In the same study, daily administration of elinzanetant at doses representing equal to or greater than 16-fold the AUC(0-24) at the human therapeutic dose showed skeletal muscle degeneration and necrosis. Convulsions were also observed in a 2-year rat study at doses representing equal to or greater than 20-fold the AUC(0-24) at the human therapeutic dose.
In cynomolgus monkeys, daily administration of elinzanetant for 39 weeks with twice daily dosing at doses equal to or greater than 60 mg/kg/day showed reduced cyclical ovarian activity. In the same study, administration of elinzanetant at 80 mg/kg/day showed diarrhoea. Diarrhoea was not observed at a lower dose of 60 mg/kg/day despite the 1.8-fold higher systemic exposure.
In the embryo-foetal developmental studies with elinzanetant in rats and rabbits no evidence of embryo-foetal toxicity occurred at doses resulting in exposures 16-fold and 1-fold the AUC(0-24) at the human therapeutic dose, respectively.
In the female rat fertility and early embryonic development study, increased percentage of pre-implantation and post-implantation embryo loss, resulting in reduced litter size, and lower foetal body weights were seen at the dose resulting in 16-fold the AUC(0-24) at the human therapeutic dose. These effects were not observed following dosing resulting in 4-fold the AUC(0-24) at the human therapeutic dose.
In the pre- and post-natal development studies in rats, F0 females showed post-implantation loss, increase in gestation length, delayed parturition and dystocia, as well as lower pup weights at doses resulting in 23-fold the AUC(0-24) at the human therapeutic dose (safety margin 6.7-fold at the NOAEL). Increase in total litter loss and corresponding decrease of pup viability on post-natal day 5 was observed in the range of human therapeutic exposure.
Following administration of radiolabelled elinzanetant to lactating rats, approximately 6% of the elinzanetant dose was excreted with milk.
In rats, a reduction in milk production of dams was seen at clinically relevant doses.
In a 2-year carcinogenicity study on elinzanetant in rats an increase in uterine neoplasms and lymphomas was reported. The findings were seen at a dose representing at least 29-fold the total AUC(0-24) at the human therapeutic dose, and are thus not considered clinically relevant. These effects were not observed at a dose representing 7-fold the total AUC(0-24) at the human therapeutic dose. The increased incidence of uterine neoplasms in aged rats undergoing reproductive senescence with pronounced body weight reduction resembles effects observed in dietary restriction studies in rats and chronic, drug-induced hypoprolactinaemia, a rat-specific mode of action, which is not relevant for humans.
No drug-related neoplasms were observed up to the highest dose of 3-fold (males) or 2-fold (females) the AUC(0-24) at the human therapeutic dose in the 26-week carcinogenicity study on elinzanetant in transgenic mice.
Environmental risk assessment studies have shown that elinzanetant may pose a risk for the aquatic environment.
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