Abstract
BACKGROUND: Elinzanetant is a dual neurokinin-1,3 receptor antagonist in development for the treatment of menopausal vasomotor symptoms. The objectives of these studies were to characterize the mass balance and biotransformation of elinzanetant. METHODS: In the clinical evaluation, whole blood, plasma, urine, and feces were collected from healthy fasted male volunteers (n = 6) following a single dose of 120 mg [(14)C]-elinzanetant oral suspension for analysis of total radioactivity and metabolite profiling. In vitro reaction phenotyping and kinetics experiments on enzymes involved in elinzanetant metabolism were performed. RESULTS: On average, 90.8% of the total radioactivity administered was recovered in excreta over 480 h, mostly via the fecal route (feces 90.4%; urine 0.4%). Elinzanetant was rapidly absorbed and extensively metabolized but remained the main circulating species in plasma, accounting for 39.1% of total radioactivity. Known principal and active metabolites M27, M30/34, and M18/21 accounted for 7.6%, 13.7%, and 4.9% of total radioactivity in plasma, respectively. All other radiolabeled plasma components were each < 3.5%, revealing the oxidation product M30/34 as the only metabolite with relevant exposure (> 10% of total radioactivity). In feces, metabolites resulting from oxidative biotransformation accounted, in sum, for ~ 40% of the dose, while elinzanetant remained the primary drug-related moiety. Results of in vitro experiments indicated that metabolism of elinzanetant was primarily mediated by cytochrome P450 3A4, with minor contribution from uridine 5'-diphospho-glucuronosyltransferase. CONCLUSIONS: Elinzanetant is metabolized mainly via oxidative biotransformation mediated by cytochrome P450 3A4, and primarily excreted in feces. The primary oxidation product M30/34 is a major human metabolite of elinzanetant. TRIAL REGISTRATION NUMBER: NCT04654897.