Population pharmacokinetic-pharmacodynamic model of elinzanetant based on integrated clinical phase I and II data.
Journal
CPT: pharmacometrics & systems pharmacology
ISSN: 2163-8306
Titre abrégé: CPT Pharmacometrics Syst Pharmacol
Pays: United States
ID NLM: 101580011
Informations de publication
Date de publication:
18 Sep 2024
18 Sep 2024
Historique:
revised:
23
07
2024
received:
14
04
2024
accepted:
26
07
2024
medline:
19
9
2024
pubmed:
19
9
2024
entrez:
19
9
2024
Statut:
aheadofprint
Résumé
Elinzanetant is a potent and selective dual neurokin-1 (NK-1) and -3 (NK-3) receptor antagonist that is currently developed for the treatment of women with moderate-to-severe vasomotor symptoms (VMS) associated with menopause. Here, we report the development of a population pharmacokinetic (popPK) model for elinzanetant and its principal metabolites based on an integrated dataset from 366 subjects (including 197 women with VMS) collected in 10 phase I or II studies. The pharmacokinetics of elinzanetant and its metabolites could be well described by the popPK model. Within the investigated dose range of 40-160 mg, the oral bioavailability of elinzanetant was dose independent and estimated to be 36.7%. The clearance of elinzanetant was estimated to be 7.26 L/h and the central and peripheral distribution volume were 23.7 and 168 L. No intrinsic or extrinsic influencing factors have been identified in the investigated population other than the effect of a high-fat breakfast on the oral absorption of elinzanetant. The popPK model was then coupled to a pharmacodynamic model to predict occupancies of the NK-1 and NK-3 receptors. After repeated once-daily administration of the anticipated therapeutic dose of 120 mg elinzanetant, the model-predicted median receptor occupancies are >99% for NK-1 and >94.8% for NK-3 during day and night-time, indicating sustained and near-complete inhibition of both target receptors during the dosing interval.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Bayer AG
Informations de copyright
© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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