Clinical Pharmacokinetics, Safety, and Tolerability of a Novel, First-in-Class TRPV4 Ion Channel Inhibitor, GSK2798745, in Healthy and Heart Failure Subjects
Clinical Pharmacokinetics, Safety, and Tolerability of a Novel, First-in-Class TRPV4 Ion Channel Inhibitor, GSK2798745, in Healthy and Heart Failure Subjects
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DOI：
10.1007/s40256-018-00320-6
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发表时间：
2019-06-01
影响因子：
3
通讯作者：
Cheriyan, Joseph
中科院分区：
文献类型：
--
作者：
Goyal, Navin;Skrdla, Pete;Cheriyan, Joseph
肺毛细血管内皮细胞瞬时受体电位香草酸4（TRPV 4）通道在介导心源性肺水肿的发生发展中起着重要作用。GSK 2798745是一种一流的、高效、选择性、口服活性TRPV 4通道阻滞剂，正在首次人体研究中进行评价（NCT 02119260）.方法GSK 2798745以随机、安慰剂对照的研究设计在三个单独的组群中以单次递增剂量（有或无食物）和以每日一次重复剂量（长达14天）给予健康志愿者，分别轻度至中度心力衰竭受试者的两个队列也接受了GSK 2798745每日一次给药，持续7天。收集了安全性、耐受性和全身暴露数据。结果在健康志愿者和心力衰竭患者中使用GSK 2798745未观察到重大安全性问题或严重不良事件。GSK 2798745全身暴露数据表明，在高达12.5 mg剂量下呈线性药代动力学，每日一次给药时蓄积小于2倍，全身半衰期与13小时相似。与高脂餐同时给药后，GSK 2798745暴露量略有增加[血药浓度-时间曲线下面积（AUC）增加14%，最大血药浓度（C-max）增加9%]。结论GSK 2798745在健康志愿者和稳定性心力衰竭患者中耐受性良好。本研究中获得的安全性和暴露数据允许在心力衰竭以及其他适应症的长期临床研究中进一步评价药物。
Introduction and ObjectivePulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channel plays a critical role in mediating the development of cardiogenic pulmonary edema. GSK2798745 is a first-in-class, highly potent, selective, orally active TRPV4 channel blocker being evaluated in a first-time-in-humans study (NCT02119260).MethodsGSK2798745 was administered in a randomized, placebo-controlled study design to healthy volunteers in three separate cohorts as single escalating doses, with and without food, and as once-daily repeat doses for up to 14days, respectively. Two cohorts of subjects with mild to moderate heart failure were also administered GSK2798745 once daily for up to 7days. Safety, tolerability, and systemic exposure data were collected.ResultsNo significant safety issues or serious adverse events were observed with GSK2798745 in healthy volunteers and patients with heart failure. GSK2798745 systemic exposure data demonstrated linear pharmacokinetics up to 12.5mg, less than twofold accumulation with once-daily dosing, and a systemic half-life of similar to 13h. There was a slight increase in GSK2798745 exposure [14% increase in area under the plasma concentration-time curve (AUC) and 9% increase in maximum observed plasma concentration (C-max)] after administration with a high-fat meal.ConclusionsGSK2798745 was well-tolerated in healthy volunteers and patients with stable heart failure. The safety and exposure data obtained in this study allow further evaluation of the drug in long-term clinical studies in heart failure as well as other indications.