First‐in‐man study of ACT ‐709478, a novel selective triple T‐type calcium channel blocker

Summary Objective Increased activity of T‐type Ca2+ 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 Ca2+ 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. Methods 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. Results The maximum plasma concentration (Cmax) 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 Cmax and area under the plasma concentration‐time curve (AUC)0‐∞ increased in a less than dose‐proportional manner. A 1.6‐fold increase in Cmax and no change in AUC0‐∞ 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. Significance ACT‐709478 exhibits good tolerability and safety after single‐dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.