This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on ISI (3)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Drug Therapy, Other  • Genetic Disorders  • Ataxia  • Randomized Controlled Trial  • Neurology, Other  • Drug Therapy  • Alert me on articles by topic

Nicholas A. Di Prospero, MD, PhD; Charlotte J. Sumner, MD; Scott R. Penzak, PharmD; Bernard Ravina, MD; Kenneth H. Fischbeck, MD; J. Paul Taylor, MD, PhD

Arch Neurol. 2007;64(6):803-808.

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 dose-limiting 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.

Clinical Trial Registry  http://clinicaltrials.gov Identifiers: NCT00015808 and NCT00078481.

Author Affiliations: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (Drs Di Prospero, Sumner, and Fischbeck) and Clinical Pharmacokinetics Research Laboratory, Pharmacy Department, National Institutes of Health Clinical Center (Dr Penzak), National Institutes of Health, Bethesda, Md; Department of Neurology, University of Rochester Medical Center, Rochester, NY (Dr Ravina); and Department of Neurology, University of Pennsylvania, Philadelphia (Dr Taylor).