作者: Zhang, Yang ; Schneider, Annika R P ; Solms, Alexander ; Lloyd, Adam ; Frechen, Sebastian ; Willmann, Stefan ; Joseph, Shiju ; Schultze-Mosgau, Marcus-Hillert ; Austin, Rupert

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.

1999-06-01·Archives of Oral Biology4区 · 医学

Tachykinin-induced responses via neurokinin-1 and -3 receptors in hamster submandibular ganglion neurones

4区 · 医学

Article

作者: T Suzuki ; T Endoh ; T Soejima

Both substance P and neurokinin A are known as neurotransmitters of the submandibular ganglion cell. In this study, the effects of neurokinin (NK) receptor-subtype agonists on hamster submandibular ganglion cells were investigated using the whole-cell patch-clamp technique. Membrane currents evoked by a ramp pulse from +50 to -100 mV (-150 mV/1000 msec) were compared in both the absence and presence of NK receptor agonist. The NK-1 receptor agonist [Sar9, Met (O2)11]-substance P, the NK-2 receptor agonist [Ala5, beta-Ala8]-alpha-neurokinin fragment 4-10, and the NK-3 receptor agonist senktide were used. The three agonists dose-dependently increased the amplitude of the inward current with a reversal potential near 0 mV. Their rank order was NK-1 = NK-3 > NK-2. Even when the external solution was replaced with Cs+ or N-methyl-D-glucamine+ instead of Na+, the NK receptor agonists also increased the amplitude of the inward current. Thus, NK-1 and NK-3 receptors are apparently coupled with non-selective cation channels in submandibular ganglion cells.

1998-02-01·Journal of Neurophysiology3区 · 医学

Substance P Regulates I _h via a NK-1 Receptor in Vagal Sensory Neurons of the Ferret

3区 · 医学

Article

作者: Weinreich, Daniel ; Jafri, M. Samir

Jafri, M. Samir and Daniel Weinreich. Substance P regulates I h via a NK-1 receptor in vagal sensory neurons of the ferret. J. Neurophysiol. 79: 769–777, 1998. Substance P (SP) hyperpolarizes ∼80% of ferret vagal sensory neurons (nodose ganglion neurons) via NK-1 receptor-mediated activation of a potassium current ( I K). A depolarizing current activated by membrane hyperpolarization could minimize the SP-induced hyperpolarization. Such a current exists in 65% of the nodose neurons ( n = 264). In this study, we examine this current and how it can interact with SP-induced membrane hyperpolarizations. This slowly developing, noninactivating inward current, designated I h, was activated maximally at about −120 mV and had a reversal potential value of −23 ± 4.4 mV ( n = 4). The time course of activation followed voltage-dependent, monoexponential kinetics. Steady-state activation curves derived from tail current analysis were well fit by a Boltzmann equation yielding a half-activation potential ( V 1/2) of−77 ± 1.5 mV and a k s value of 18 ± 0.5 ( n = 8). In the presence of 1 mM cesium, the current was completely abolished. These parameters are consistent with those derived for I h in other neurons. Substance P (200 nM) reduced the magnitude of I h elicited by membrane hyperpolarizations to about −110 mV but did not affect the magnitude of I h elicited by hyperpolarizations to more negative potentials. Tail current analysis revealed that this effect was the result of a SP-induced shift of the I h activation curve to more negative membrane potentials. The V 1/2 value for I h was shifted by −20 ± 1.4 mV in the presence of SP with no change in k s (18 ± 0.7; n = 5). The SP effect on I h, like its effect on I K, was blocked reversibly by 10 nM CP99,994, a NK-1 antagonist, and was mimicked by the NK-1 agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASMSP; 200 nM). I h was not affected by NK-2 or NK-3 selective agonists ( n = 4 for each) nor was the effect of SP on I h reduced by an NK-2 antagonist ( n = 4). These results show that SP activates a NK-1 receptor coupled to the I h channel. Thus NK-1 receptor activation in ferret vagal afferents not only leads to membrane hyperpolarization but it also can enhance synergistically this inhibitory effect by decreasing I h.

100 项与 NK-003 相关的药物交易

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