Population pharmacokinetic-pharmacodynamic model of elinzanetant based on integrated clinical phase I and II data

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.