Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Parexel International GmbH, Berlin, Germany.
Epilepsia. 2019 May;60(5):968-978. doi: 10.1111/epi.14732. Epub 2019 Apr 20.
Increased activity of T-type Ca channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. ACT-709478 is an orally available triple T-type Ca channel blocker. The aim of this first-in-man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of ACT-709478 in healthy subjects.
This double-blind, placebo-controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1-400 mg ACT-709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60 mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests.
The maximum plasma concentration (C ) was reached within 3 to 4 hours (≤60 mg) and within 20 to 28 hours (>60 mg), and across all dose levels the terminal half-life (95% confidence interval) ranged from 36 (29-45) to 43 (22-86) hours. Multiple peaks were observed and C and area under the plasma concentration-time curve (AUC) increased in a less than dose-proportional manner. A 1.6-fold increase in C and no change in AUC was observed in fed compared to fasted conditions. A significant correlation (P < 0.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo.
ACT-709478 exhibits good tolerability and safety after single-dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.
T 型钙通道活性增加与特发性全面性癫痫有关，因此阻断这些通道可能是一种新的治疗选择。ACT-709478 是一种口服可用的三型 T 型钙通道阻滞剂。本项首次人体研究的目的是调查健康受试者单次口服 ACT-709478 的药代动力学、药效学、耐受性和安全性。
这是一项双盲、安慰剂对照、随机研究，纳入 65 名健康男性受试者。按顺序将 1-400mg ACT-709478 或安慰剂单次口服给予 8 名受试者（6 名服用活性药物，2 名服用安慰剂）。在交叉部分，还测试了 60mg 剂量的食物影响。定期进行药代动力学评估和安全性评估的血液和唾液采样。使用一系列药效学测试评估对中枢神经系统的影响。
最大血浆浓度（C ）在 3 至 4 小时（≤60mg）和 20 至 28 小时（>60mg）内达到，在所有剂量水平下，终末半衰期（95%置信区间）范围为 36（29-45）至 43（22-86）小时。观察到多个峰值，C 和血浆浓度-时间曲线下面积（AUC）呈非剂量比例增加。与空腹相比，进食状态下 C 增加 1.6 倍，AUC 无变化。使用线性回归建立了血浆和唾液浓度之间的显著相关性（P<0.0001）。所有不良事件均为短暂性，且为轻度或中度。未发现生命体征、临床实验室、遥测或心电图有与治疗相关的变化。与基线或安慰剂相比，药效学测试的结果未显示出相关的平均变化。
ACT-709478 单次给药后具有良好的耐受性和安全性，其药代动力学和药效学特征值得进一步研究。
