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Eliapixant Sale

(Synonyms: 依利哌嗪,BAY 1817080) 目录号 : GC62950

Eliapixant (BAY1817080) is a highly potent and selective P2X3 receptor antagonist with a mean IC50 of 8 nM.

Eliapixant Chemical Structure

Cas No.:1948229-21-7

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5 mg
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产品描述

Eliapixant (BAY1817080) is a highly potent and selective P2X3 receptor antagonist with a mean IC50 of 8 nM.

[1] Alyn Morice, et al. Eur Respir J . 2021 Nov 18;58(5):2004240.

Chemical Properties

Cas No. 1948229-21-7 SDF
别名 依利哌嗪,BAY 1817080
分子式 C22H21F3N4O3S 分子量 478.49
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Research Update

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

Eur Respir J 2021 Nov 18;58(5):2004240.PMID:33986030DOI:10.1183/13993003.04240-2020.

Background: ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of Eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres. Methods: In period A, patients received placebo for 2 weeks then Eliapixant 10 mg for 1 week. In period B, patients received Eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A-B (n=20) or B-A (n=20). The primary efficacy end-point was change in cough frequency assessed over 24 h. The primary safety end-point was frequency and severity of adverse events (AEs). Results: 37 patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg: 25% (90% CI 11.5-36.5%); p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41-49% receiving Eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5-21% with Eliapixant; all were mild. Conclusions: Selective P2X3 antagonism with Eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC.

Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers

Sci Rep 2021 Oct 6;11(1):19877.PMID:34615939DOI:10.1038/s41598-021-99177-0.

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, Eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that Eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether Eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that Eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

First-in-human study of Eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: Tolerability, safety and pharmacokinetics

Br J Clin Pharmacol 2022 Oct;88(10):4552-4564.PMID:35437837DOI:10.1111/bcp.15358.

Aims: Neuronal hypersensitisation due to adenosine triphosphate-dependent P2X3 receptor signalling plays a significant role in several disorders including chronic cough and endometriosis. This first-in-human study of Eliapixant (BAY 1817080) investigated the tolerability, safety and pharmacokinetics (PK) of single doses of Eliapixant, including the effect of food and coadministration with a CYP3A inhibitor on Eliapixant relative bioavailability. Methods: In this randomised, double-blind phase I study (NCT02817100), 88 healthy male subjects received single ascending doses of immediate-release Eliapixant (10-800 mg) tablets or placebo under fasted conditions, with food (low-fat continental or high-fat American breakfast) or with itraconazole (fasted state). PK parameters, dose proportionality, adverse events and taste assessments (taste strips; dysgeusia questionnaire) were evaluated. Results: Eliapixant had a long half-life (23.5-58.9 h [fasted state]; 32.8-43.8 h [high-fat breakfast]; 38.9-46.0 h [low-fat breakfast]). Less than dose-proportional increases in maximum plasma concentrations (Cmax ) and area under the concentration-time curve from time 0 to infinity (AUC[0-inf] ) were observed with ascending Eliapixant doses. We observed a pronounced food effect with the high-fat breakfast (4.1-fold increased Cmax ; 2.7-fold increased AUC[0-inf] ), a smaller food effect with the low-fat breakfast and a mild-to-moderate effect of itraconazole coadministration on Eliapixant (1.1-1.2-fold increased Cmax ; 1.7-fold increased AUC from 0 to 72 h). Eliapixant was well tolerated with minimal impact on taste perception. Conclusion: The PK profile, particularly the long half-life, and favourable tolerability with no taste-related adverse events, supports the further development of Eliapixant in disorders with underlying P2X3 receptor-mediated neuronal hypersensitisation.

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

Clin Pharmacokinet 2022 Aug;61(8):1143-1156.PMID:35624408DOI:10.1007/s40262-022-01126-1.

Background and objective: There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as Eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of Eliapixant in healthy volunteers. Methods: We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of Eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. Results: Peak plasma concentrations of Eliapixant were reached 3-4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of Eliapixant showed low peak-trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. Conclusions: Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled Eliapixant to progress to clinical trials in patients with refractory chronic cough. Clinical trial registration: Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017).

Preclinical and Clinical Pharmacokinetics and Bioavailability in Healthy Volunteers of a Novel Formulation of the Selective P2X3 Receptor Antagonist Eliapixant

Eur J Drug Metab Pharmacokinet 2023 Jan;48(1):75-87.PMID:36469250DOI:10.1007/s13318-022-00805-5.

Background and objectives: The potent, selective P2X3 receptor antagonist Eliapixant (BAY 1817080) is under development for conditions characterized by neuronal hypersensitization. As prominent food effects and limited bioavailability in the fasted state were observed with immediate-release Eliapixant tablets, a novel formulation was needed. Accordingly, several novel Eliapixant formulations were assessed by in vitro and animal studies in a structured way. The most promising of the formulations was then investigated in a phase I study designed to assess its pharmacokinetics, food effect, and bioavailability in healthy volunteers. Methods: In vitro non-sink dissolution tests were performed with two amorphous solid dispersion (ASD) granule prototypes compared with pure crystalline Eliapixant as a surrogate for the immediate-release formulation. Subsequently, the drug exposure of novel Eliapixant formulations under fed and fasted conditions in rats and dogs was assessed to confirm improvements in bioavailability versus the suspension-based formulation. A novel Kollidon VA64®-based Eliapixant formulation was identified from the preclinical studies and compared with the original tablet formulation in an open-label, partially randomized, threefold, crossover phase I study, in which healthy males received single oral doses (25-400 mg, fasted/fed). Pharmacokinetic parameters, absolute bioavailability (using an intravenous [13C715N]-eliapixant microdose), relative bioavailability (novel versus original formulation), effect of food, and adverse events (AEs) were evaluated. Results: The non-sink dissolution test demonstrated that the two ASD formulations had an improved dissolution rate compared with pure crystalline Eliapixant, with a Kollidon VA64-based prototype having the highest dissolution rate. Further testing of this prototype in animal studies confirmed an approximately twofold higher bioavailability compared with the suspension-based formulation. In the phase I study, 30 subjects were randomized. With the novel Kollidon VA64® formulation (400 mg; fasted), area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax) were up to 3.1-fold and 1.7-fold higher, respectively, than with the original formulation (fed). AUC increased dose proportionally between 25 and 100 mg, and less than dose proportionally from 100 to 400 mg. Food had no clinically relevant effect on the novel formulation, with AUC increasing 1.3-fold and Cmax 2.1-2.4-fold (time to maximum concentration was delayed by 1.5-2.25 h). Absolute bioavailability with the novel formulation (100 mg) was 50%. AEs occurred in 57% of patients; most were mild in severity. Conclusions: The novel Eliapixant formulation substantially improved bioavailability compared with immediate-release Eliapixant and may be administered with/without food. Clinical trial registration: Clinicaltrials.gov: NCT03773068 (initial registration: 12 December 2018).