Idebenone

Abstract

Idebenone is a benzoquinone compound which has been investigated in elderly patients with dementia. Its precise mechanism(s) of action remains unknown, but in vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and/or cerebral metabolism and facilitate memory and learning. In the small number of studies available for evaluation, idebenone was generally superior to placebo and comparable with bifemelane, oxiracetam and nebracetam on the basis of a number of objective and subjective tests and rating scales in patients with mild to moderate cognitive decline. Clinical trial results indicate that patients with mild dementia seem more likely to respond than those with greater functional decline. The degree of benefit conferred by idebenone is often difficult to determine, but in those who respond, improvement is generally mild to moderate. Therapy with idebenone appears well tolerated for up to 2 years, and no changes in vital signs or laboratory values have been seen in clinical trials. In view of the lack of a proven agent to limit or halt the progression of dementia in the elderly, idebenone may warrant consideration in patients with mild cognitive dysfunction on the basis of preliminary evidence of predominantly mild improvement of functional status in some patients and good tolerability. However, further well designed studies, including comparisons with newer and commonly used agents, such as tacrine, are required to better define the role of idebenone in this complex area of treatment. Idebenone is a benzoquinone compound structurally unrelated to other agents undergoing investigation for the treatment of senile cognitive disorders. The precise mechanism by which this drug acts remains unknown. In vitro studies suggest it may work as an antioxidant or oxygen free radical scavenger and may improve cerebral metabolism. In rats, idebenone diminished ischaemia-induced amnesic behaviour and improved learning dysfunction attributed to deficits in acetylcholine and serotonin (5-hydroxytryptamine; 5-HT). In 7 patients with dementia following cerebral haemorrhage/infarction, increased levels of dopamine, serotonin and noradrenaline (norepinephrine) metabolites were measured in cerebrospinal fluid after 1 to 2 months’ treatment with idebenone 90 mg/day. However, no clear correlation between neurotransmitter metabolite levels in cerebrospinal fluid and dementia severity could be demonstrated on the Hasegawa Dementia Rating Scale. Peak plasma idebenone concentrations (C_max) of 290 to 399 µg/L were achieved within 1.3 to 2.1 hours after doses of 30 to 50mg, and plasma concentrations were dose-dependent over a range of 10 to 100mg. A ‘second peak’ phenomenon has been observed after drug administration to healthy volunteers as well as patients with moderate renal or hepatic failure. This is likely to be the result of enterohepatic recirculation and may account for reports of variation in the estimated time to reach C_max. Administration of idebenone after food appears to enhance absorption. Hepatic metabolism of idebenone results in side chain oxidation, sulphate and glucuronide conjugation and subsequent renal excretion. Several metabolites, with no apparent biological activity, have been identified. The extent and/or rate of metabolism and excretion of idebenone and metabolites have not been reported. Elimination half-life values for idebenone show wide variation (range 2.6 to 21.7 hours); however, given the apparent lack of drug accumulation occurring with multiple dose administration, it is unlikely that this variation will be clinically significant. Neither moderate renal or hepatic failure nor cardiovascular disorders caused any significant alteration in measured pharmacokinetic parameters compared with those in healthy volunteers. Idebenone has been studied in patients with mild to moderate senile dementia of the Alzheimer type and vascular dementia. Inherent problems in this therapeutic area result from the lack of adequate tools necessary to make a definitive diagnosis and to comprehensively evaluate drug treatment. The efficacy of idebenone was measured using a battery of neuropsychological and behavioural tests, subjective rating scales and, in Japanese studies, clinical symptom group analysis. Improvements due to drug treatment were reported in all trials reviewed but, because they were ill defined, their impact on the patient’s level of function was difficult to determine. Significant improvements over baseline scores, in some or all tests, were reported in patients receiving idebenone in noncomparative trials, and the drug was generally superior to placebo. Additionally, 50% (n = 51) of patients in 1 study considered idebenone treatment beneficial compared with no change or deterioration in 66% of placebo recipients (n = 48), a feeling that was corroborated by their relatives. Slight benefit was observed in the majority of patients receiving idebenone in clinical trials on the basis of clinical symptom group (psychiatric, neurological, subjective and activity of daily living) analysis. Idebenone 90 mg/day has been compared with bifemelane 150 mg/day, oxiracetam 800 and 1600 mg/day and nebracetam 400 mg/day. Improvements in assessment parameters were seen in all treatment groups compared with baseline (but none of these studies included a placebo control); however, idebenone was shown to be superior (on the basis of 2 of 5 rating scales) only to oxiracetam 1600 mg/day. Maximum benefit from idebenone therapy is likely to be apparent after 3 to 6 months. Some further improvement may be observed for up to 9 months, after which symptoms appear to stabilise. A carry-over effect has been observed, based on continued improvement in a small number of patients’ test scores 30 days after stopping drug therapy. However, decline in cognitive function after stopping treatment has also been noticed. Several studies indicate that an inverse relationship may exist between the level of impairment and expected response to idebenone, and it has been suggested that patients with dementia of vascular origin may respond more favourably than those with senile dementia of the Alzheimer type. However, these are only preliminary indications and as yet, it is not possible to predict reliably which patients may benefit from idebenone. Generally, idebenone has been reported to be well tolerated in clinical trials lasting up to 2 years; however, not all investigators reported data on adverse events. Gastrointestinal complaints (gastralgia, vomiting, abdominal colic, diarrhoea) were most frequently reported, occurring in about 7% (n = 339) of idebenone and 4% (n = 150) of placebo recipients. Other unwanted symptoms included anxiety/irritability, headache, polyuria, drowsiness/dizziness, confusion and tachycardia. These adverse events were mild in nature, requiring neither dose adjustment nor adjunctive therapy. Both improvements and deterioration in sleep were reported during idebenone treatment. Of approximately 750 patients treated with idebenone, 1 patient withdrew after 90 days’ treatment because of mild psychomotor agitation and 3 others because of unspecified adverse events. No significant changes in vital signs or laboratory values have been noted during therapy with idebenone. In clinical trials, idebenone 30 to 300 mg/day (most commonly 90 mg/day) has been administered orally in divided doses. Preliminary pharmacokinetic data indicate that dose or dose interval adjustment is not required in patients with moderate renal or hepatic failure or cardiovascular disease. However, further confirmation of dosage recommendations is warranted in these disease conditions because of the frequency with which they occur in older patients.