Pharmacokinetic evaluation of idebenone.

IMPORTANCE OF THE FIELD: Idebenone is a synthetic short chain benzoquinone that acts as an electron carrier in the mitochondrial electron transport chain, thereby, facilitating the production of ATP. In addition, idebenone is an antioxidant and can inhibit lipid peroxidation and may protect cell membranes and mitochondria from oxidative damage. High dose idebenone (Catena(®)) is approved in Canada for the symptomatic treatment of Friedreich's ataxia and is currently under clinical investigation for use in a number of mitochondrial and neuromuscular diseases. AREAS COVERED IN THIS REVIEW: This review summarizes the pharmacology, pharmacokinetic and clinical efficacy/safety data of idebenone and its metabolites and provides an update of the clinical trials completed and in progress. WHAT THE READER WILL GAIN: Following oral administration, idebenone is rapidly metabolized via oxidative shortening by a number CYP isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) to yield QS10, QS8, QS6 and QS4. Idebenone and these metabolites concomitantly undergo conjugation via glucuronidation and sulfatation to yield conjugated moieties represented as idebenone-C, QS10-C, QS8-C, QS6-C and QS4-C. Previous reports in the literature were only able to quantify plasma concentrations of idebenone measured together with its conjugates. More recently, highly sensitive and specific liquid chromatography method with tandem mass spectrometric methods have been developed, allowing the quantification of the parent molecule idebenone and its main metabolite QS10, separately. TAKE HOME MESSAGE: After absorption, idebenone is rapidly metabolized by first pass metabolism and shows dose-proportional pharmacokinetics in healthy subjects in daily doses up to 2250 mg. The recent development of advanced analytical techniques allows the detection of idebenone and unconjugated metabolites in plasma and consequently opens the possibility for evaluation of pharmacokinetic/pharmacodynamic relationships which will be helpful to further understand the metabolism and therapeutic potential of idebenone. In clinical studies, idebenone was safe and well tolerated at doses up to 2250 mg/day.