J Neurol (2009) 256 [Suppl 1]:31–35 DOI 10.1007/s00415-009-1006-z JON 1006 Klaus Kutz Jürgen Drewe Pierre Vankan Pharmacokinetic properties and metabolism of idebenone Introduction Idebenone (2,3-dimethoxy-5-methyl-6-(10-hydroxy- decyl)-1,4-benzoquinone) is a synthetic analogue of ubiquinone, an essential constituent of the electron transport chain and a vital cell membrane anti-oxidant. It has been shown that patients with Friedreich ataxia (FRDA) have a deficiency in biosynthesis of adenosine triphosphate (ATP) [1]. Idebenone is theorised to im- prove deficiencies in electron flow and to reduce oxida- tive stress in patients with FRDA. Several open-label studies found that 5 mg/kg/day of idebenone reduced cardiac hypertrophy in FRDA [2–4]. These studies also suggested that higher doses of idebenone may be neces- sary for patients to experience the full clinical benefit of idebenone treatment, particularly as it relates to im- provements in neurological function [3, 5–7]. This hy- pothesis was confirmed in a placebo-controlled trial in paediatric patients with FRDA [8]. Information on the pharmacokinetics of the phar- macologically active parent idebenone has been limited. Parent idebenone is rapidly metabolised through oxida- tion and side chain shortening to the inactive metabo- lites QS10, QS8, QS6, and QS4 (Fig. 1) [9]. Both parent idebenone and its metabolites exist free or conjugated to sulfates and glucuronides. The analytical methods pub- lished to date were not sensitive enough to reliably mea- ■ Abstract Four phase 1 studies were conducted to assess the pharmacokinetics and metabolism of idebenone (including parent drug and inactive metabolites QS10, QS6, and QS4) and to evalu- ate the safety of a wide range of idebenone doses and regimens in healthy adult men. After a single oral dose of idebenone 150 mg, 750 mg, or 1050 mg in fasted or fed subjects, blood samples were taken for up to 72 hours. In one study, after a single oral dose and a 7-day washout period, subjects received repeated doses of idebenone 150 mg or 750 mg every 8 hours for 14 days. In the repeated-dose study, urine samples also were taken. Plasma and urine samples were analysed with the use of liquid chromatography with tandem mass spectrometry. Non-compartmental standard pharmacokinetic meth- ods were used. In these studies, a total of 69 subjects ranging in age from 19 to 41 years (body weight, 57–94.6 kg) were included. Plasma concentrations of parent idebenone were low but increased in propor- tion to dose and increased approxi- mately five-fold in the presence of food. Total QS4 was the main metabolite in plasma and urine. The most common adverse events were loose stool, fatigue, headache, and disturbances in attention. Idebenone was well tolerated in single oral doses up to 1050 mg and in repeated daily doses up to 2250 mg. Idebenone showed linear pharmacokinetics after single and repeated oral dosing. Administra- tion after a meal resulted in the highest exposure to parent idebenone. ■ Key words idebenone · Friedreich ataxia · pharmacokinetics · healthy subjects K. Kutz, MD AccelPharm Hebelstrasse 15A Basel, Switzerland J. Drewe, MD, MSc University Hospital Basel, Switzerland P. Vankan, PhD () Santhera Pharmaceuticals Ltd Hammerstrasse 47 4410 Liestal, Switzerland Tel.: +41-61/906 8957 Fax: +41-61/906 8951 E-Mail: Pierre.Vankan@santhera.com