Skip to main content
SpringerLink
Log in

Pharmacokinetics and metabolism of idebenone in healthy male subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Idebenone is a synthetic analogue of ubiquinone that may be beneficial in the treatment of Friedreich’s ataxia. Since in previous pharmacokinetic trials only lower doses were studied, it was the aim of this study to evaluate the pharmacokinetics of idebenone in higher doses of up to 2,250 mg/day.

Methods

In this open, randomized trial, 25 healthy male subjects received first either a single oral dose of 150 mg or 750 mg of idebenone, then the same dose given at 8-h intervals for 14 days.

Results

Idebenone and its metabolites appeared in the plasma quickly. Over 99% of parent idebenone was metabolized, indicating a high first-pass effect. Cmax and AUC0−t values for parent idebenone and its metabolites increased in a dose-proportional manner. There was virtually no accumulation of parent drug or metabolites following multiple dosing.

Conclusions

Idebenone exhibited dose-dependent pharmacokinetics in daily doses up to 2,250 mg. In 6/14 subjects, adverse events of mild to moderate severity were observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (1996) Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 335:1169–1175

    Article  PubMed  CAS  Google Scholar 

  2. Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423–1427

    Article  PubMed  CAS  Google Scholar 

  3. Rötig A, Sidi D, Munnich A, Rustin P (2002) Molecular insights into Friedreich’s ataxia and antioxidant-based therapies. Trends Mol Med 8:221–224

    Article  PubMed  Google Scholar 

  4. Pandolfo M (2008) Friedreich ataxia. Arch Neurol 65:1296–1303

    Article  PubMed  Google Scholar 

  5. Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, Schapira AH (1999) Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA 96:11492–11495

    Article  PubMed  CAS  Google Scholar 

  6. Schulz JB, Dehmer T, Schols L, Mende H, Hardt C, Vorgerd M, Burk K, Matson W, Dichgans J, Beal MF, Bogdanov MB (2000) Oxidative stress in patients with Friedreich ataxia. Neurology 55:1719–1721

    PubMed  CAS  Google Scholar 

  7. Di Prospero NA, Fischbeck KH (2005) Therapeutics development for triplet repeat expansion diseases. Nat Rev 6:756–765

    Article  CAS  Google Scholar 

  8. Suno M, Nagaoka A (1984) Inhibition of lipid peroxidation by a novel compound, idebenone (CV-2619). Jap J Pharmacol 35:196–198

    PubMed  CAS  Google Scholar 

  9. Zs-Nagy I (1990) Chemistry, toxicology, pharmacology and pharmacokinetics of idebenone: a review. Arch Gerontol Geriatr 11:177–186

    Article  PubMed  CAS  Google Scholar 

  10. Sugiyama Y, Fujita T (1985) Stimulation of the respiratory and phosphorylating activities in rat brain mitochondria by idebenone (CV-2619), a new agent improving cerebral metabolism. FEBS Lett 184:48–51

    Article  PubMed  CAS  Google Scholar 

  11. Gillis JC, Benefield P, McTavish D (1994) Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders. Drugs Aging 5:133–152

    Article  PubMed  CAS  Google Scholar 

  12. Gutzmann H, Hadler D (1998) Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl 54:301–310

    PubMed  CAS  Google Scholar 

  13. Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, Weiner MF, Zamrini E, Thomas RG (2003) Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 61:1498–1502

    PubMed  CAS  Google Scholar 

  14. Weyer G, Babej-Dolle RM, Hadler D, Hofmann S, Herrmann WM (1997) A controlled study of 2 doses of idebenone in the treatment of Alzheimer’s disease. Neuropsychobiol 36:73–82

    Article  CAS  Google Scholar 

  15. Buyse G, Mertens L, Di Salvo G, Matthijs I, Weidemann F, Eyskens B, Goossens W, Goemans N, Sutherland GR, Van Hove JL (2003) Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring. Neurology 60:1679–1681

    Article  PubMed  CAS  Google Scholar 

  16. Hausse AO, Aggoun Y, Bonnet D, Sidi D, Munnich A, Rotig A, Rustin P (2002) Idebenone and reduced cardiac hypertrophy in Friedreich’s ataxia. Heart 87:346–349

    Article  PubMed  CAS  Google Scholar 

  17. Mariotti C, Solari A, Torta D, Marano L, Fiorentini C, Di Donato S (2003) Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology 60:1676–1679

    PubMed  CAS  Google Scholar 

  18. Arnold P, Boulat O, Maire R, Kuntzer T (2006) Expanding view of phenotype and oxidative stress in Friedreich’s ataxia patients with and without idebenone. Schweiz Arch Neurol Psychiatr 157:169–176

    Google Scholar 

  19. Artuch R, Aracil A, Mas A, Colome C, Rissech M, Monros E, Pineda M (2002) Friedreich’s ataxia: idebenone treatment in early stage patients. Neuropediatrics 33:190–193

    Article  PubMed  CAS  Google Scholar 

  20. Rustin P, Rötig A, Munnich A, Sidi D (2002) Heart hypertrophy and function are improved by idebenone in Friedreich’s ataxia. Free Radical Res 36:467–469

    Article  CAS  Google Scholar 

  21. Di Prospero N, Baker A, Jeffries N, Fischbeck KH (2007) Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol 6:878–886

    Article  PubMed  CAS  Google Scholar 

  22. Kobayashi T, Yoshida K, Mitani M, Torii H, Tanayama S (1985) Metabolism of idebenone (CV-2619), a new cerebral metabolism improving agent: isolation and identification of metabolites in the rat and dog. J Pharmacobiodyn 8:448–456

    PubMed  CAS  Google Scholar 

  23. Boni J, Maugeri A, Zingali G, Ramelli L, Gherardi S (1992) Steady-state pharmacokinetics of idebenone in healthy volunteers. Arch Gerontol Geriatr 15:197–205

    Article  PubMed  CAS  Google Scholar 

  24. Pisano P, Durand A, Autret E, Desnuelle C, Pinsard N, Serratrice G, Legout V, Joubert M, Blin O (1996) Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy. Eur J Clin Pharmacol 51:167–169

    Article  PubMed  CAS  Google Scholar 

  25. Torii H, Yoshida K, Kobayashi T, Tsukamoto T, Tanayama S (1985) Disposition of idebenone (CV-2619), a new cerebral metabolism improving agent, in rats and dogs. J Pharmacobiodyn 8:457–467

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, University Hospital Basel, Basel, Switzerland

    Michael Bodmer, Manfred Dreier & Jürgen Drewe

  2. AccelPharm, Basel, Switzerland

    Klaus W. Kutz

  3. Santhera Pharmaceuticals (Switzerland) Ltd, Liestal, Switzerland

    Pierre Vankan & Klaus W. Kutz

  4. Clinical Pharmacology and Toxicology, University Hospital Basel, Hebelstr. 2, CH-4031, Basel, Switzerland

    Jürgen Drewe

Authors
  1. Michael Bodmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Vankan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manfred Dreier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Klaus W. Kutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jürgen Drewe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jürgen Drewe.

Additional information

Competing interest: P.V. is employee of Santhera Pharmaceuticals, K.W.K. is an independent consultant to Santhera Pharmaceuticals, J.D. received a research grant from Santhera Pharmaceuticals, M.B. and M.D. have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bodmer, M., Vankan, P., Dreier, M. et al. Pharmacokinetics and metabolism of idebenone in healthy male subjects. Eur J Clin Pharmacol 65, 493–501 (2009). https://doi.org/10.1007/s00228-008-0596-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-008-0596-1

Keywords

Search

Navigation