A positron emission tomography (PET) study to assess the degree of neurokinin-1 (NK1) receptor occupancy in the human brain after single doses of netupitant to healthy male subjects.

Abstract

9054 Background: Netupitant (NETU) is a highly selective neurokinin 1 (NK1) receptor antagonist for the prevention of nausea and vomiting associated with emetogenic chemotherapy. In this study, PET imaging with the NK1 receptor-binding–selective tracer 11C-GR205171 was used to determine the levels and the duration of central NK1 receptor occupancy (RO) achieved by therapeutic doses of NETU. Methods: This was a single dose, randomized, open-label, PET study investigating the degree of NK1 RO in human brain after single oral doses of NETU (100, 300 or 450 mg) in 6 healthy male subjects. PET scans and blood samples for NETU determination were obtained up to 96 hrs post dose. The Patlak model was used to define the net uptake rate of 11C-GR205171 in the brain regions of interest while the percent of NK1 RO was calculated as the relative difference between the uptake rate at baseline and post-treatment administration. Results: NETU plasma concentrations over the 100 mg to 450 mg dose range were comparable with those obtained in previous single dose studies. A NK1 RO of 90% or higher was achieved with all tested single oral doses in the majority of the outlined brain regions 6 hrs after dosing (corresponding to netupitant Cmax). All doses had a long duration of blockade of NK1 receptors with the 300 mg dose showing moderate (62%) to high (94%) NK1 RO for all investigated brain regions at 96 hrs post dose. The relationship between NETU concentration and NK1 RO, assessed using a sigmoid Emax model, indicated that in the striatum, the reference brain area with the highest NK1 receptor expression, a concentration of 225 μg/L of NETU corresponded to an NK1 RO of 90%. This data suggests that a single oral dose between 100 and 300 mg NETU would be needed to reach 90% NK1 RO levels in human brain. Conclusions: PET results demonstrate that NETU is a potent agent targeting NK1 receptors with a high degree of occupancy for a long duration. NETU, given as single doses of 100 to 450 mg was well tolerated.