![]() ![]() ![]() 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. Elimination via both routes was estimated to be complete by Day 29-30 post-dose. Approximately half the radioactivity administered orally as -netupitant was recovered from urine and faeces within 120 h of dosing. ![]() 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. Renal clearance is not a significant elimination route for netupitant-related entities. Eliminationįollowing 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. 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. Mean C max 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. The ratios were time dependent with values decreasing gradually beyond 24 h post-dose, indicating that netupitant is being rapidly metabolized. 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. In vitro metabolism studies have suggested that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 are involved in the metabolism of netupitant. 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). The third major metabolite, M2, is >97% bound to plasma proteins. 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. DistributionĪfter 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). Netupitant AUC 0-∞ and C max increased by 1.1 fold and 1.2 fold, respectively, after a high fat meal. In a pooled analysis, females had a higher netupitant exposure compared to males there was a 1.31-fold increase in C max, a 1.02 fold increase for AUC and a 1.36 fold increase in half-life. In 82 healthy subjects given a single oral dose of netupitant 300 mg, maximum plasma netupitant concentration (C max) was 486 ☒68 ng/mL (mean ± SD) and median time to maximum concentration (T max) was 5.25 hours, the AUC was 15032 ± 6858 h.ng/mL. There was a supra-proportional increase in C max and AUC parameters for doses from 10 mg to 300 mg. Plasma concentrations followed a first order absorption process and reached C max in approximately 5 hours. In single dose oral studies, netupitant was measurable in plasma between 15 minutes and 3 hours after dosing. National Library of Medicine.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%. ^ "Akynzeo (netupitant/palonosetron) capsules" (PDF).Archived from the original on 19 March 2020. Archived from the original on 18 October 2020. ^ "Akynzeo- netupitant and palonosetron capsule Akynzeo- fosnetupitant and palonosetron injection".^ "Fosnetupitant/Palonosetron (Intravenous Route)"."Netupitant-palonosetron (NEPA) for Preventing Chemotherapy-induced Nausea and Vomiting: From Clinical Trials to Daily Practice". ^ Aapro M, Jordan K, Scotté F, Celio L, Karthaus M, Roeland E (2022). ![]()
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