Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study.
Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study.
复制标题
DOI：
10.1007/s40262-022-01126-1
复制
发表时间：
2022-08
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
对于顽固性慢性咳嗽，尚无获得许可的治疗方法；标签外治疗的疗效有限，并且可能产生不良反应。通过 P2X3 受体的过多三磷酸腺苷信号传导与顽固性慢性咳嗽有关，并且选择性 P2X3 受体拮抗剂如 eliapixant (BAY 1817080) 正在研究中。该研究的目的是调查健康志愿者增加重复口服剂量的 eliapixant 的安全性和耐受性。我们对 47 名健康男性个体进行了一项重复剂量、双盲、随机、安慰剂对照研究。受试者每天两次递增口服剂量的 eliapixant（10、50、200 和 750 mg）或安慰剂，持续 2 周。主要结局是不良事件的频率和严重程度。其他结果包括药代动力学和味觉障碍的评估，这种情况发生在选择性较低的 P2X3 受体拮抗剂吉法匹克 (gefapixant) 身上。首次和后续剂量给药后 3-4 小时达到 eliapixant 的血浆峰浓度。通过多次给药，约 6 天后达到稳态血浆浓度，并且在 200 和 750 mg 时达到预计达到 ≥ 80% P2X3 受体占有率（疗效所需的水平）的血浆浓度。血浆浓度随剂量增加的增加小于剂量比例。多次给药后，eliapixant 的平均血浆浓度显示出较低的峰谷波动，并且 200 毫克和 750 毫克剂量的平均血浆浓度相似。 Eliapixant 耐受性良好，味觉相关不良事件发生率低。 Eliapixant（200 和 750 mg）产生的血浆浓度在 24 小时内覆盖了预测的治疗阈值，具有良好的安全性和耐受性。这些结果使 eliapixant 能够进入难治性慢性咳嗽患者的临床试验。 ClinicalTrials.gov：NCT03310645（首次注册：2017 年 10 月 16 日）。在线版本包含可在 10.1007/s40262-022-01126-1 获取的补充材料。对于长期（慢性）咳嗽的患者，几乎没有有效的治疗方法。人们认为，慢性咳嗽是由于神经变得过于敏感，在没有必要的情况下错误地引起咳嗽而引起的。我们在 47 名健康男性身上测试了一种名为 eliapixant 的新药。 Eliapixant 可减少导致慢性咳嗽的过度神经信号传导。我们寻找 eliapixant 的副作用并测量它在体内的表现。我们特别寻找与味觉相关的副作用，因为吉法匹克（gefapixant）是一种与埃拉匹克类似的药物，会影响味觉。参与者每天两次服用四剂 eliapixant 中的一剂或安慰剂，持续两周。服药后 3-4 小时血液中 eliapixant 浓度达到最高，约 6 天后浓度稳定。在两个最高剂量下，eliapixant 在体内达到的浓度应该足够高，足以对慢性咳嗽患者起作用。 eliapixant 和安慰剂之间的副作用通常相似。与味觉相关的副作用很轻微，无需治疗即可消失。这项研究的积极结果意味着 Eliapixant 可以在慢性咳嗽患者中进行测试。在线版本包含可在 10.1007/s40262-022-01126-1 获取的补充材料。
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. 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. 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. 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. Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017). The online version contains supplementary material available at 10.1007/s40262-022-01126-1. There are few effective treatments for patients with a long-term (chronic) cough. It is thought that chronic cough is caused by nerves becoming oversensitive, wrongly causing a cough when there is no need. We tested a new drug called eliapixant in 47 healthy men. Eliapixant reduces the excessive nerve signaling responsible for chronic cough. We looked for side effects of eliapixant and measured how it behaves in the body. In particular we looked for side effects relating to the sense of taste because gefapixant, a similar drug to eliapixant, can affect taste. Participants took one of four eliapixant doses or a placebo twice daily for 2 weeks. The highest levels of eliapixant in the blood were seen 3–4 h after taking the drug, and stable concentrations were seen after about 6 days. At the two highest doses, eliapixant reached concentrations in the body that should be high enough to work in patients with chronic cough. Side effects were generally similar between eliapixant and placebo. Taste-related side effects were mild and went away without needing treatment. The positive results of this study meant that eliapixant could be tested in patients with chronic cough. The online version contains supplementary material available at 10.1007/s40262-022-01126-1.
登录
查看更多内容
影响因子：
2.7
作者：
Burnstock G
通讯作者：
Burnstock G
DOI：
10.1186/1745-9974-3-5
发表时间：
2007-03-23
期刊：
Cough (London, England)
影响因子：
--
作者：
Everett CF;Kastelik JA;Thompson RH;Morice AH
通讯作者：
Morice AH
影响因子：
16.2
作者：
Freeman R;Durso-Decruz E;Emir B
通讯作者：
Emir B
DOI：
10.1111/j.1471-0528.2008.01878.x
发表时间：
2008-10-01
影响因子：
5.8
作者：
Ballard, K. D.;Seaman, H. E.;Wright, J. T.
通讯作者：
Wright, J. T.
影响因子：
14.2
作者：
Hilton, Emma C. Y.;Baverel, Paul G.;Smith, Jaclyn A.
通讯作者：
Smith, Jaclyn A.