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Safety, tolerability, and pharmacokinetics of idebenone in a dose‐escalation trial in patients with Friedreich's ataxia
Author(s) -
Di Prospero N.A.,
Sumner C.,
Atkinson A.,
Fischbeck K.,
Taylor J. P.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.150
Subject(s) - idebenone , frataxin , ataxia , tolerability , pharmacokinetics , pharmacology , medicine , dosing , oxidative stress , trinucleotide repeat expansion , toxicity , chemistry , adverse effect , biochemistry , iron binding proteins , psychiatry , transferrin , allele , gene
Friedreich's ataxia is a progressive neurodegenerative disorder caused by a GAA trinucleotide expansion within the fraxatin gene. This mutation results in a loss of the frataxin protein within mitochondria leading to reduced activity of key enzymes, excess production of free radicals, and defective oxidative phosphorylation. Recent studies suggest that the antioxidant, idebenone, may prevent disease progression and greater efficacy may be seen with higher doses. In order to explore the full dose range, 81 patients divided evenly among adults, adolescents, and children participated in an unblinded, 1 day dose‐escalation trial of oral idebeonone divided TID. No dose limiting toxicity was observed, and the maximum allowed dose of 75 mg/kg was achieved in all cohorts. Analysis of serum levels of total idebenone revealed a large variation in absorption of the drug. This variation precluded complete analysis of plasma concentration obtained during repetitive dosing; however, the terminal half‐life following the last dose was consistent across the dose levels, indicating dose proportionality. A follow‐up study in 15 patients revealed that a dose of 60 mg/kg/day was safe and well tolerated for 1 month. These findings indicate that higher doses of this drug should be explored for efficacy in Friedreich's ataxia and other diseases associated with oxidative stress. Clinical Pharmacology & Therapeutics (2005) 77 , P68–P68; doi: 10.1016/j.clpt.2004.12.150