Abstract：
Inhibition of activated factor XI reduces thrombogenesis while maintaining physiological hemostasis, with the expectation of reduced bleeding risk compared with standard of care in the clinical setting. Asundexian (BAY 2433334), an activated factor XI inhibitor, is in clinical development for the prevention of thromboembolic events. The effect of asundexian and its plasma metabolite M10 on cardiac repolarization and potential interactions with the hNav1.5 sodium, hCav1.2 calcium, and human ether-à-go-go-related gene (hERG) potassium channels was investigated in vitro. Additionally, asundexian effects on cardiac parameters and electrocardiogram were examined in telemetered beagle dogs. A randomized, placebo-controlled, 4-way crossover, thorough QT study in healthy adults evaluated the influence of 50 and 150 mg of asundexian on the corrected QT interval, including 400 mg of moxifloxacin as positive control. Across all studies, asundexian and M10 were not associated with any effects on cardiac repolarization. The largest in vitro effects of asundexian (approximately 20% inhibition) were seen for hCav1.2 and hERG. Throughout the thorough QT study, the upper limits of the one-sided 95% confidence interval of placebo-corrected mean changes from baseline in Fridericia corrected QT for 50 and 150 mg of asundexian were below Δ = 10 milliseconds. Asundexian demonstrated favorable safety and tolerability profiles.
摘要：
抑制激活的因子XI减少血栓形成，同时维持生理止血，与临床护理标准相比，预期出血风险降低。Asundexian(BAY2433334),激活的因子XI抑制剂，预防血栓栓塞事件的临床开发。asundexian及其血浆代谢产物M10对心脏复极化的影响以及与hNav1.5钠的潜在相互作用，hCav1.2钙，并在体外研究了人类ether-à-go-go相关基因（hERG）钾通道。此外,在遥测比格犬中检查了asundexian对心脏参数和心电图的影响。一个随机的，安慰剂对照,4路交叉，在健康成年人中进行全面的QT研究，评估了50和150毫克asundexian对校正QT间期的影响，包括400毫克莫西沙星作为阳性对照。在所有研究中，asundexian和M10对心脏复极无影响.对于hCav1.2和hERG，观察到asundexian的最大体外作用（约20％的抑制作用）。在整个全面的QT研究中，在Fridericia校正的QT中,50和150mgasundexian的安慰剂校正自基线的平均变化的单侧95%置信区间的上限低于Δ=10毫秒.Asundexian表现出良好的安全性和耐受性。
