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Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study
Clinical Pharmacokinetics ( IF 4.5 ) Pub Date : 2022-05-28 , DOI: 10.1007/s40262-022-01126-1
Christian Friedrich 1 , Klaus Francke 1 , Isabella Gashaw 1, 2 , Christian Scheerans 1 , Stefan Klein 1 , Lueder Fels 1 , Jaclyn A Smith 3 , Thomas Hummel 4 , Alyn Morice 5
Affiliation  

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).



中文翻译:

P2X3 受体拮抗剂 Eliapixant (BAY 1817080) 在健康受试者中的安全性、药效学和药代动力学:双盲随机研究

背景与目的

顽固性慢性咳嗽没有获得许可的治疗方法;超说明书疗法的疗效有限并且可能产生不良反应。通过 P2X3 受体的过量三磷酸腺苷信号传导与难治性慢性咳嗽有关,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在健康志愿者中增加重复口服剂量的 eliapixant 的安全性和耐受性。

方法

我们对 47 名健康男性进行了一项重复剂量、双盲、随机、安慰剂对照的研究。受试者接受每日两次递增口服剂量的 eliapixant(10、50、200 和 750 mg)或安慰剂,持续 2 周。主要结果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评估,这些都发生在选择性较低的 P2X3 受体拮抗剂吉法匹生中。

结果

在第一次和后续剂量给药后 3-4 小时达到了 eliapixant 的血浆峰浓度。多次给药后,约 6 天后达到稳态血浆浓度,预计达到 ≥ 80% P2X3 受体占有率(疗效所需的水平)的血浆浓度在 200 和 750 毫克时达到。随着剂量增加血浆浓度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低峰谷波动,并且在 200 和 750 毫克剂量时相似。Eliapixant 耐受性良好,与味觉相关的不良事件发生率低。

结论

Eliapixant(200 和 750 mg)在 24 小时内产生的血浆浓度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。

临床试验注册

Clinicaltrials.gov:NCT03310645(初始注册:2017 年 10 月 16 日)。

更新日期:2022-05-31
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