Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetics of EPI‐589 in Healthy Participants

Abstract EPI‐589 attenuates oxidative stress due to the radical scavenging activity of the reduced form and affects mitochondrial energy metabolism as a substrate of quinone‐oxidoreductases. Given the effects of EPI‐589 on oxidative stress and mitochondrial dysfunction, EPI‐589 shows promise as a potential therapy for patients with amyotrophic lateral sclerosis. This phase 1 study evaluated the safety, tolerability, and pharmacokinetic profiles of EPI‐589. Sixty‐eight healthy participants were randomly assigned to EPI‐589 or placebo. All adverse events were mild or moderate in severity, and no severe adverse events were reported. After single‐dose administration under fasting conditions, time to maximum plasma concentration (t max ) occurred 0.25 to 1.00 hour after administration. Both peak plasma concentration (C max ) and area under the plasma concentration–time curve (AUC) were approximately linear with increases in single doses over a dose range of 250–1000 mg. Under fed conditions, the C max decreased to 62.6% of the C max under fasting conditions, the AUC was slightly increased, and the t max was delayed by 1 hour. When EPI‐589 was administered daily on days 1 and 7 with twice‐daily dosing on days 2 through 6, the plasma trough concentration appeared to reach steady state by day 3. At both doses studied (500 mg twice daily and 750 mg twice daily), C max, t max , and AUC were generally comparable between day 1 and day 7 and between the Japanese and White participants. EPI‐589 was well tolerated as a single daily dose up to 1000 mg and as twice‐daily doses up to 750 mg, with a linear pharmacokinetic profile.