Elinzanetant, a dual neurokinin NK-1,3 receptor antagonist under development for moderate-to-severe vasomotor symptoms (VMS) associated with menopause, has undergone thorough mass balance and biotransformation characterization in a Phase 1 clinical study. The study, detailed in a recent publication, investigated the recovery, absorption, metabolism, and excretion of a single 120 mg oral dose of [14C]-labeled elinzanetant in healthy male subjects.
The research provides critical insights into the drug's pharmacokinetic properties and metabolic pathways, essential for understanding its safety and efficacy profile. These findings support the ongoing clinical development of elinzanetant as a potential treatment for menopausal VMS.
Mass Balance and Excretion
The study achieved a high recovery rate, with an average of 90.8% of the administered radioactivity recovered in excreta within 480 hours. Fecal excretion was the primary route, accounting for approximately 90.4% of the recovered dose, while urinary excretion was negligible at approximately 0.4%. This indicates that elinzanetant and its metabolites are primarily eliminated through the feces, with minimal renal clearance.
Pharmacokinetics and Metabolism
Pharmacokinetic analysis revealed that elinzanetant is rapidly absorbed, followed by a biphasic/multiphasic decline in plasma concentrations over 240 hours. The geometric mean half-life of elinzanetant was 37.1 hours, consistent with once-daily dosing. Metabolite profiling identified several metabolites, with M30/34 being the most prominent in plasma, accounting for approximately 11% of total drug-related radioactivity. In feces, a wide range of metabolites were observed, indicating extensive biotransformation.
Enzyme Involvement
In vitro studies using human hepatocytes and CYP3A inhibitors demonstrated that CYP3A4 is the primary enzyme responsible for elinzanetant metabolism, with a minor contribution from CYP3A5. Glucuronidation, mediated by UGT enzymes, was estimated to contribute around 5-12% of metabolic clearance.
Tolerability
Elinzanetant was well-tolerated in the study, with only two mild, unrelated adverse events reported: mild constipation and mild epistaxis.
Implications for Clinical Development
The comprehensive characterization of elinzanetant's mass balance and metabolism provides valuable information for its clinical development. The findings support the once-daily dosing regimen and highlight the importance of CYP3A4 in its metabolism. The favorable tolerability profile observed in the study further supports the continued investigation of elinzanetant as a potential treatment for vasomotor symptoms associated with menopause.
"These data demonstrate that the primary route of excretion for total radioactivity is via feces, with the parent compound and a range of metabolites identified," the researchers noted in the publication. "Recovery of total radioactivity from urine was negligible in all subjects."
The study's results contribute to a deeper understanding of elinzanetant's pharmacological properties, paving the way for optimized dosing strategies and a more informed assessment of its potential benefits and risks in clinical use.
