Eli Lilly and Company, Indianapolis, Indiana, USA.
Eli Lilly and Company, Lilly UK, Windlesham, Surrey, UK.
Clin Transl Sci. 2018 Jan;11(1):46-53. doi: 10.1111/cts.12497. Epub 2017 Aug 30.
Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070.
在一项健康受试者中进行的、受试/研究者双盲、平行分组、多剂量递增研究中，探索了 EP4 拮抗剂 LY3127760 的安全性、耐受性和药理学特征。队列由 13 名随机分配到 LY3127760、塞来昔布（400mg）或安慰剂（9:2:2 比例）的患者组成，疗程为 28 天。LY3127760 具有良好的耐受性；最常见的不良反应为胃肠道相关，与塞来昔布相似。与安慰剂相比，LY3127760 在脂多糖/前列腺素 E2 刺激后增加了体外肿瘤坏死因子-α的释放，提示 EP4 受体呈剂量依赖性阻断。与安慰剂相比，24 小时尿前列腺素 E 代谢物排泄略有增加；前列腺素 I2 代谢物被抑制；血栓素 A2 代谢物无变化。对钠和钾排泄的影响与塞来昔布相似。我们得出结论，LY3127760 对前列腺素合成和肾钠潴留的影响与塞来昔布相似。这些数据支持在 II 期试验中探索 LY3127760 的每日剂量为 60mg 至 600mg。该试验的注册号：NCT01968070。
