Centre for Human Drug Research, Leiden, the Netherlands.
Acesion Pharma ApS, Copenhagen, Denmark.
Br J Clin Pharmacol. 2024 Apr;90(4):1027-1035. doi: 10.1111/bcp.15973. Epub 2024 Jan 8.
AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca activated K (K2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial.
Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected.
AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h.
AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the I channel.
AP30663 是一种新型化合物，通过靶向小电导钙激活钾 (K2) 通道，用于心房颤动的药理学转换。本扩展阶段 1 研究的目的是测试与首次人体试验相比，AP30663 的更高单剂量。
16 名健康男性志愿者随机分为 2 组：AP30663 静脉 6 毫克/公斤和 8 毫克/公斤单剂量与安慰剂相比。收集安全性、药代动力学和药效学数据。
AP30663 与轻微且短暂的输注部位反应相关，没有其他不良事件的聚集，但在 6 毫克/公斤剂量水平下，估计平均最大 QTcF 间隔延长 45.2ms（95%置信区间 31.5-58.9），8 毫克/公斤剂量水平下延长 50.4ms（95%置信区间 36.7-64.0）。药代动力学呈剂量比例关系，终末半衰期约为 3 小时。
AP30663 剂量高达 8 毫克/公斤与轻微且短暂的输注部位反应和 QTcF 间隔增加有关。支持信息表明，QTc 效应可能是由于对 I 通道的非靶标抑制所致。
