Mass Balance Recovery, Absorption, Metabolism, and Excretion of Elinzanetant in Healthy Human Volunteers and in vitro Biotransformation

  • Eur J Drug Metab Pharmacokinet. 2025 Jan;50(1):91-103. doi: 10.1007/s13318-024-00930-3.
Simone I Schulz  1 ,  Marcus-Hillert Schultze-Mosgau  2 ,  Anna Engelen  1 ,  Nand Singh  3 ,  Steve Pawsey  4 ,  Klaus Francke  5 ,  Ruth Lock  6 ,  Antje Rottmann  7
Affiliations
  • 1. Preclinical Development-Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany.
  • 2. Early Clinical Development, Bayer AG, Berlin, Germany. [email protected].
  • 3. Medical Department, Quotient Sciences, Nottingham, UK.
  • 4. NeRRe Therapeutics Ltd, Stevenage, UK.
  • 5. Early Clinical Development, Bayer AG, Berlin, Germany.
  • 6. Aucuba Sciences Ltd, London, UK.
  • 7. Preclinical Development-Drug Metabolism and Pharmacokinetics, Bayer AG, Berlin, Germany.
PMID: 39719488 DOI: 10.1007/s13318-024-00930-3
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 [14C]-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.

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