Netupitant PET imaging and ADME studies in humans

Abstract

Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy-induced nausea and vomiting. Two studies were conducted to evaluate the brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography (PET) imaging with the NK1 receptor-binding–selective tracer [11C]-GR205171 was used to evaluate the brain penetration of different doses of netupitant (100, 300, and 450 mg) and to determine the NK1-RO duration. A NK1-RO of 90% or higher was achieved with all doses in the majority of the tested brain regions at Cmax, with a long duration of RO. The netupitant minimal plasma concentration predicted to achieve a NK1-RO of 90%, C90%, in the striatum was 225 ng/mL; after administration of netupitant 300 mg, concentrations exceeded the C90%. In the ADME study, a single nominal dose of [14C]-netupitant 300 mg was used to assess its disposition. Absorption was rapid and netupitant was extensively metabolized via Phase I and II hepatic metabolism. Elimination of >90% was predicted at day 29 and was principally via hepatic/biliary route (>85%) with a minor contribution of the renal route (<5%). In conclusion, these studies demonstrate that netupitant is a potent agent targeting NK1 receptors with long lasting RO. In addition, netupitant is extensively metabolized and is mainly eliminated through the hepatic/biliary route and to a lesser extent via the kidneys.

Netupitant/Palonosetron

“…1 Additionally, coadministration with food, presence of cancer, or subsequent administration of chemotherapy have no effect on the pharmacokinetic parameters of netupitant and palonosetron. 1 Netupitant monotherapy has linear pharmacokinetics in regard to C max and AUC in single doses ranging from 100 to 450 mg. 18 After oral administration of netupitant, T max is about 5 hours. 1,18 Netupitant and its metabolites (M1, M2, and M3) are highly bound in plasma proteins (99.5% netupitant, 97.5% metabolites).…”

“…1 Netupitant monotherapy has linear pharmacokinetics in regard to C max and AUC in single doses ranging from 100 to 450 mg. 18 After oral administration of netupitant, T max is about 5 hours. 1,18 Netupitant and its metabolites (M1, M2, and M3) are highly bound in plasma proteins (99.5% netupitant, 97.5% metabolites). 1 Netupitant undergoes significant metabolism to a multitude of metabolites via both phase 1 and phase 2 processes.…”

“…The primary metabolites M1, M2, and M3 account for 29%, 14%, and 33%, respectively, of the circulating exposure to netupitant; these metabolites are active in animal models. 1,18 The approximate half-life after a single dose of netupitant in cancer patients is 80 hours. 1 Netupitant 300 mg has a long duration of receptor occupancy at 96 hours, which contributes to its duration of effect.…”

“…1 Netupitant 300 mg has a long duration of receptor occupancy at 96 hours, which contributes to its duration of effect. 18 Following oral administration of radiolabeled netupitant, half of the radioactivity is recovered in feces and urine 120 hours post dose; 70% and 4% of the drug are recovered in feces and urine, respectively, by 336 hours; and 86.5% and 4.8% of the drug are recovered in feces and urine, respectively, by 30 days post dose. Radioactivity is recovered primarily as metabolites.…”

“…17,18 Netupitant is present in the frontal and occipital cortex, the striatum, the anterior cingulate, and the lateral and medial temporal cortex. 18 Palonosetron is a 5-HT 3 receptor antagonist that inhibits the serotonin secreted from stimulation by chemotherapy.…”