Chemical formula: C₃₀H₃₂F₆N₄O Molecular mass: 578.603 g/mol PubChem compound: 6451149
Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors. Chemotherapeutic substances produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.
Delayed emesis has been associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.
Netupitant was shown to cross the blood brain barrier with a NK 1 receptor occupancy of 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after administration of 300 mg netupitant.
Absolute netupitant bioavailability data are not available in humans; based on data from two studies with intravenous netupitant, the bioavailability in humans is estimated to be greater than 60%. In single dose oral studies, netupitant was measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations followed a first order absorption process and reached Cmax in approximately 5 hours. There was a supra-proportional increase in Cmax and AUC parameters for doses from 10 mg to 300 mg.
In 82 healthy subjects given a single oral dose of netupitant 300 mg, maximum plasma netupitant concentration (Cmax) was 486 ±268 ng/mL (mean ± SD) and median time to maximum concentration (Tmax) was 5.25 hours, the AUC was 15032 ± 6858 h.ng/mL. In a pooled analysis, females had a higher netupitant exposure compared to males; there was a 1.31-fold increase in Cmax, a 1.02 fold increase for AUC and a 1.36 fold increase in half-life.
Netupitant AUC0-∞ and Cmax increased by 1.1 fold and 1.2 fold, respectively, after a high fat meal.
After a single oral 300 mg dose administration in cancer patients, netupitant disposition was characterised by a two compartment model with an estimated median systemic clearance of 20.5 L/h and a large distribution volume in the central compartment (486 L). Human plasma protein binding of netupitant and its two major metabolites M1 and M3 is >99% at concentrations ranging from 10 to 1500 ng/mL. The third major metabolite, M2, is >97% bound to plasma proteins.
Three metabolites have been detected in human plasma at netupitant oral doses of 30 mg and higher (the desmethyl derivative, M1; the N-oxide derivative, M2; the OH-methyl derivative, M3). In vitro metabolism studies have suggested that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 are involved in the metabolism of netupitant. After administration of a single oral dose of 300 mg netupitant, mean plasma netupitant/plasma radioactivity ratios ranged from 0.13 to 0.49 over 96 h post-dose. The ratios were time dependent with values decreasing gradually beyond 24 h post-dose, indicating that netupitant is being rapidly metabolized. Mean Cmax was approximately 11%, 47% and 16% of the parent for M1, M2 and M3 respectively; M2 had the lowest AUC relative to the parent (14%) whereas M1 and M3 AUC were approximately 29% and 33% of the parent, respectively. M1, M2 and M3 metabolites were all shown to be pharmacologically active in an animal pharmacodynamic model, where M3 was most potent and M2 least active.
Following administration of a single dose, netupitant is eliminated from the body in a multi-exponential fashion, with an apparent mean elimination half-life of 88 hours in cancer patients. Renal clearance is not a significant elimination route for netupitant-related entities. The mean fraction of an oral dose of netupitant excreted unchanged in urine is less than 1%; a total of 3.95% and 70.7% of the radioactive dose was recovered in the urine and faeces, respectively. Approximately half the radioactivity administered orally as [14C]-netupitant was recovered from urine and faeces within 120 h of dosing. Elimination via both routes was estimated to be complete by Day 29-30 post-dose.
Maximum concentrations and total exposure of netupitant were increased in subjects with mild (n=8), moderate (n=8), and severe (n=2) hepatic impairment compared to matching healthy subjects, although there was pronounced individual variability in both hepatically-impaired and healthy subjects. Exposure to netupitant (Cmax, AUC0-t and AUC0-∞) compared to matching healthy subjects was 11%, 28% and 19% higher in mild and 70%, 88% and 143% higher in moderate hepatically-impaired subjects, respectively. As such, no dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Limited data exist in patients with severe hepatic impairment (Child Pugh score ≥9).
No specific studies were performed to evaluate netupitant in patients with renal impairment. In the ADME trial, less than 5% of all netupitant-related material was excreted in urine and less than 1% of the netupitant dose was eliminated unchanged in the urine and therefore any accumulation of netupitant or metabolites after a single dose would be negligible. Furthermore, the population PK study showed no correlation between PK parameters of netupitant and markers of renal dysfunction.
Netupitant has been evaluated in patients with end-stage renal disease.
Effects in non-clinical studies based on safety pharmacology and single and repeated dose toxicity were observed only at exposures considered in excess of the maximum human exposure, indicating little relevance to clinical use. Phospholipidosis (foamy macrophages) has been observed with the administration of netupitant after repeated administration in rats and dogs. The effects were reversible or partially reversible after the recovery period. The significance of these findings in humans is unknown.
Non-clinical studies indicate that netupitant and its metabolites and the combination with palonosetron only at very high concentrations may block ion channels involved in ventricular de- and re-polarisation and prolong action potential duration. Reproductive studies in animals with netupitant do not indicate direct or indirect harmful effects with respect to fertility, parturition or postnatal development. An increased incidence of positional foetal abnormalities of the limbs and paws, fused sternebrae and agenesis of accessory lung lobe were observed following daily administration of netupitant in rabbits at 10 mg/kg/day and higher during the period of organogenesis. In a pilot dose range finding study in rabbits, cleft palate, microphtalmia and aphakia were observed in four foetuses from one litter in the 30 mg/kg/day group. The relevance of these findings in humans is unknown. No data from animal studies with netupitant are available regarding placental transfer and lactation. Netupitant is not mutagenic.
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