Idebenone (2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-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). Idebenone is theorised to improve deficiencies in electron flow and to reduce oxidative stress in patients with FRDA. Several open-label studies found that 5 mg/kg/day of idebenone reduced cardiac hypertrophy in FRDA. These studies also suggested that higher doses of idebenone may be necessary for patients to experience the full clinical benefit of idebenone treatment, particularly as it relates to improvements in neurological function. This hypothesis was confirmed in a placebo-controlled trial in paediatric patients with FRDA.
Information on the pharmacokinetics of the pharmacologically active parent idebenone has been limited. Parent idebenone is rapidly metabolised through oxidation and side chain shortening to the inactive metabolites QS10, QS8, QS6, and QS4 (Fig. 1). Both parent idebenone and its metabolites exist free or conjugated to sulfates and glucuronides. The analytical methods published to date were not sensitive enough to reliably measure parent idebenone; therefore, it was possible to determine only the total amount of idebenone (parent drug plus conjugated idebenone) in plasma.
For this reason, the goals of the present clinical pharmacology program were to assess more accurately the pharmacokinetics and metabolism of idebenone (parent drug and metabolites) and to evaluate the safety of idebenone, administered as single oral doses of up to 1050 mg under fasted and fed conditions, and of up to 2250 mg daily for 2 weeks, in healthy male subjects.
Four different clinical phase 1 studies were performed (Table 1). Study SNT-I-002 and SNT-I-004 were single-group studies in which healthy male subjects received one dose of idebenone after intake of a continental breakfast; study SNT-I-001 was a parallel-group, cross-over study of two dose levels of idebenone (150 mg and 750 mg) in which subjects received a single dose of idebenone once after fasting and once after a meal; study SNT-I-003 was a parallel-group study in which subjects received first a single oral dose of idebenone, followed after a 7-day washout period by repeated doses three times daily (tid) at 8-hour intervals for 14 days. The repeated-dose study was recently published. The morning dose was given after intake of a continental breakfast. All studies were carried out in accordance with the ethical standards established in the 1964 Declaration of Helsinki, and they followed current International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) Guidelines. Informed consent was obtained from all subjects as a pre-condition for participation in any of these studies.
Blood samples for pharmacokinetics were taken up to 72 hours after dosing. In study SNT-I-003, urine was quantitatively collected after the last drug intake. Plasma and urine samples were deep frozen (at −80 °C) pending analysis. Safety assessments, including adverse event (AE) monitoring, 12-lead electrocardiograms (ECGs), and evaluation of vital signs and laboratory values (haematology, serum chemistry, and urinalysis), were performed.
For determination of parent idebenone in plasma, 10 μL of ethylenediaminetetraacetic acid (EDTA) was added to the samples after thawing to avoid enzymatic degradation of the conjugates. For determination of total metabolites, a glucuronidase/sulfatase enzyme solution was added to plasma and urine samples for de-conjugation. Idebenone and its metabolites QS10, QS6, and QS4 were analysed by liquid chromatography with tandem mass spectrometry (LCMS/MS).
Klaus Kutz, Jürgen Drewe, Pierre Vankan. J Neurol (2009) 256 [Suppl 1]:31–35