Safety, tolerability, and pharmacokinetics of high-dose idebenone in patients with Friedreich ataxia

Background: Friedreich ataxia ( FA) is a progressive, multisystem degenerative disorder in which oxidative stress is believed to have a role. Recent clinical studies indicate that the antioxidant idebenone, administered at 5 mg/ kg per day, reduces the cardiac hypertrophy that occurs in FA, but improvement in neurologic measures is unclear. Some studies suggest that higher doses of idebenone may be more effective, but pharmacology and toxicology at higher doses have not been investigated in human beings. Objective: To determine the safety, tolerability, and pharmacokinetics of increasing doses of idebenone in subjects with FA. Design: Open-label, phase 1A dose-escalation trial followed by an open-label, 1-month phase 1B trial. Setting: National Institutes of Health Clinical Center, Bethesda, Md. Patients: Phase 1A included 78 subjects with FA ( 24 adults, 27 adolescents, and 27 children), and phase 1B included 15 subjects with FA ( 5 adults, 5 adolescents, and 5 children). Interventions: Oral idebenone was administered to groups of 3 subjects in each age cohort during day 1. In phase 1A, the dose was increased in 10-mg/ kg increments in each successive dose group to a maximum of 75 mg/ kg. In phase 1B, oral idebenone was administered at 60 mg/ kg divided in 3 doses per day for 1 month. Main Outcome Measures: We studied the type, number, and frequency of adverse events, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, area under the curve, and half- life. Results: In the first phase of the study, no doselimiting toxicity was observed and the maximum allowed dose of 75 mg/ kg was achieved in all cohorts. Plasma levels of total idebenone were found to increase proportional to drug dose up to 55 mg/ kg. Variability in absorption of the drug was observed, but drug half- life was relatively consistent across dose levels. In the second phase of the study, 14 of 15 subjects with FA tolerated idebenone at a dose of 60 mg/ kg per day for 1 month. All adverse events were mild, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, and half- life did not differ significantly across age cohorts. Conclusions: These findings indicate that higher doses of idebenone lead to a proportional increase in plasma levels up to 55 mg/ kg per day and that high- dose idebenone is well- tolerated in patients with FA. These findings are essential to planning efficacy trials of high- dose idebenone in FA and other degenerative diseases in which oxidative damage has been implicated.