Netupitant PET imaging and ADME studies in humans

Area of Science:

• Neuroscience
• Pharmacology
• Radiochemistry

Background:

• Netupitant is a novel, selective NK1 receptor antagonist.
• It is being developed for chemotherapy-induced nausea and vomiting (CINV).

Purpose of the Study:

• Evaluate brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans.
• Determine the dose-dependent brain penetration and NK1 receptor occupancy duration.

Main Methods:

• Positron emission tomography (PET) imaging using [(11)C]-GR205171 tracer.
• Assessed brain penetration and NK1 receptor occupancy at doses of 100, 300, and 450 mg.
• A single [(14)C]-netupitant dose evaluated drug disposition.

Main Results:

• High NK1 receptor occupancy (>90%) achieved in most brain regions at Cmax with all doses.
• A plasma concentration of 225 ng/mL (C90%) was predicted for 90% striatal occupancy; 300 mg dose exceeded this.
• Netupitant is rapidly absorbed, extensively metabolized (Phase I/II), and primarily eliminated hepatically/biliary (>85%) with minor renal excretion (<5%).

Conclusions:

• Netupitant is a potent NK1 receptor antagonist with long-lasting brain occupancy.
• The drug undergoes extensive hepatic metabolism and is mainly eliminated via the biliary route.