Willmann Stefan, Lloyd Adam, Austin Rupert, Joseph Shiju, Solms Alexander, Zhang Yang, Schneider Annika R P, Frechen Sebastian, Schultze-Mosgau Marcus-Hillert
Bayer AG, Pharmaceuticals, Pharmacometrics/Modeling and Simulation, Wuppertal/Leverkusen/Berlin, Germany.
BAST Inc. Limited, Leicester, UK.
CPT Pharmacometrics Syst Pharmacol. 2024 Dec;13(12):2137-2149. doi: 10.1002/psp4.13226. Epub 2024 Sep 18.
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.
依林扎那坦是一种强效且具有选择性的双重神经激肽-1（NK-1）和-3（NK-3）受体拮抗剂，目前正被开发用于治疗患有与更年期相关的中度至重度血管舒缩症状（VMS）的女性。在此，我们基于来自10项I期或II期研究中收集的366名受试者（包括197名患有VMS的女性）的综合数据集，报告了依林扎那坦及其主要代谢物的群体药代动力学（popPK）模型的建立。依林扎那坦及其代谢物的药代动力学可以通过popPK模型得到很好的描述。在40 - 160mg的研究剂量范围内，依林扎那坦的口服生物利用度与剂量无关，估计为36.7%。依林扎那坦的清除率估计为7.26L/h，中央分布容积和外周分布容积分别为23.7L和168L。除了高脂早餐对依林扎那坦口服吸收的影响外，在所研究的人群中未发现其他内在或外在影响因素。然后将popPK模型与药效学模型相结合，以预测NK-1和NK-3受体的占有率。在每天一次重复给予预期治疗剂量120mg依林扎那坦后，模型预测的NK-1受体占有率在白天和夜间均>99%，NK-3受体占有率>94.8%，表明在给药间隔期间对两种靶受体均有持续且近乎完全的抑制作用。
