Adme Study of [14c] Netupitant Administered as an oral 300 Mg Suspension to Healthy Male Subjects

ABSTRACT Background Netupitant (NETU) is a highly selective neurokinin 1 receptor antagonist developed to provide protection from nausea and vomiting induced by emetogenic chemotherapy. The objectives of the study were to investigate the pharmacokinetic (PK) profile, the mass balance recovery, the excretion pathways and the metabolism of [14C]NETU in an open-label study in 6 healthy male subjects receiving a single-nominal-dose of 300 mg as oral suspension. Methods Plasma, urine and feces samples were collected up to 336h after dosing, plus two additional 24h excreta collections until 696h. Total radioactivity was measured by liquid scintillation counting (liquid samples) and after combustion in oxygen (non-liquid samples). PK parameters for NETU and its metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Results [14C]-NETU is rapidly absorbed with peak in plasma concentration ranging between 2h and 5.5h post dose. Elimination is mainly via the feces, with approximately 71% of the total radioactivity recovered at 696h. Urinary elimination accounts for less than 4% of total radioactivity. Cumulative percent of total radioactivity suggests that approximately half of the administered dose was recovered within 120h and, based on an extrapolation, elimination was completed by 696h. NETU undergoes extensive metabolism forming phase I and II metabolites. The main metabolites of NETU are M1 (N-demethylated NETU), M2 (NETU N-oxide) and M3 (monohydroxy NETU) which, on average, account respectively for 29%, 14% and 33% of the NETU plasma exposure. Phase I metabolites observed include those formed through N-demethylation, mono and di-hydroxylation, N-oxidation, desaturation, N-formylation, oxidation and reduction to a keto group and oxidation to an acid. Phase II metabolites include those formed by glucuronidation and conjugation to a hexose group. Conclusions These data indicate that the hepatic/biliary route, rather than renal clearance is the major elimination route for drug-related entities. NETU undergoes extensive metabolism via phase I and II metabolic reactions with M1, M2 and M3 as the main circulating metabolites. NETU was well tolerated. Disclosure C. Giuliano: Helsinn employee, S. Calcagnile: Helsinn employee, All other authors have declared no conflicts of interest.