Two Decades-Long Journey from Riluzole to Edaravone: Revisiting the Clinical Pharmacokinetics of the Only Two Amyotrophic Lateral Sclerosis Therapeutics
The recent approval of edaravone has provided an intravenous option to treat amyotrophic lateral sclerosis (ALS) in addition to the existing oral agent, riluzole. The present work was primarily undertaken to provide a comprehensive clinical pharmacokinetic summary of the two approved ALS therapeutics. The key objectives of the review were to (i) tabulate the clinical pharmacokinetics of riluzole and edaravone with emphasis on absorption, distribution, metabolism and excretion (ADME) properties; (ii) provide a comparative scenario of the pharmacokinetics of the two drugs wherever possible; and (iii) provide perspectives and introspection on the gathered clinical pharmacokinetic data of the two drugs with appropriate conjectures to quench scientific curiosity. Based on this review, the following key highlights were deduced: (i) as a result of both presystemic metabolism and polymorphic hepatic cytochrome P450 (CYP) metabolism, the oral drug riluzole exhibited more inter-subject variability than that of intravenous edaravone; (ii) using various parameters for comparison, including the published intravenous data for riluzole, it was apparent that edaravone was achieving the desired systemic concentrations to possibly drive the local brain concentrations for its efficacy in ALS patients with lesser variability than riluzole; (iii) using scientific conjectures, it was deduced that the availability of intravenous riluzole may not be beneficial in therapy due to its fast systemic clearance; (iv) on the contrary, however, there appeared to be an opportunity for the development of an oral dosage form of edaravone, which may potentially benefit the therapy option for ALS patients by avoiding hospitalization costs; and (v) because of the existence of pharmaco-resistance for the brain entry in ALS patients, it appeared prudent to consider combination strategies of edaravone and/or riluzole with suitable P-glycoprotein efflux-blocking drugs to gain more favorable outcomes in ALS patients.
Compliance with Ethical Standards
No external funding was used in the preparation of this manuscript.
Conflict of interest
Ranjeet P. Dash, R. Jayachandra Babu and Nuggehally R. Srinivashave declare no conflicts of interest or competing interests relevant to the content of this review article.
- 6.Hughes JT. Pathology of amyotrophic lateral sclerosis. In: Rowland LP, editor. Human motor neuron diseases. Advances in neurology, vol. 36. New York: Raven Press; 1982. p. 61–74.Google Scholar
- 9.Boss B, Sunderland P, Heath J. Alterations of neurologic function. In: McCance K, Huether S, editors. Pathophysiology: the biologic basis for disease in adults and children. 2nd ed. St. Louis: Mosby-Year Book. Inc.; 1994. p. 576.Google Scholar
- 14.Louwerse ES, Weverling GJ, Bossuyt PM, Meyjes FE, de Jong JM. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol. 1995;52:559–64. https://doi.org/10.1001/archneur.1995.00540300031009.CrossRefPubMedGoogle Scholar
- 24.Rilutek® (riluzole): product monograph. sanofi-aventis Canada Inc., Laval. May 11, 2010. Available online from http://products.sanofi.ca/en/rilutek.pdf. Accessed 20 Apr 2018.
- 25.van Kan HJ, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH, Guchelaar HJ. Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis. Br J Clin Pharmacol. 2005;59(3):310–3. https://doi.org/10.1111/j.1365-2125.2004.02233.x.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.van Kan HJ, van den Berg LH, Groeneveld GJ, van der Straaten RJ, van Vught PW, Lie-A-Huen L, et al. Pharmacokinetics of riluzole: evidence for glucuronidation as a major metabolic pathway not associated with UGT1A1 genotype. Biopharm Drug Dispos. 2008;29(3):139–44. https://doi.org/10.1002/bdd.594.CrossRefPubMedGoogle Scholar
- 29.Wei M, Xiao Y. Clinical study on the effect of low molecular weight heparin calcium injection on plasma concentration of edaravone in patients with cerebral infarction. Zhongguo Yiyuan Yaoxue Zazhi. 2011;31(23):1933–6.Google Scholar
- 30.Tang DQ, Li YJ, Li Z, Bian TT, Chen K, Zheng XX, et al. Study on the interaction of plasma protein binding rate between edaravone and taurine in human plasma based on HPLC analysis coupled with ultrafiltration technique. Biomed Chromatogr. 2015;29(8):1137–45. https://doi.org/10.1002/bmc.3401.CrossRefPubMedGoogle Scholar
- 31.Komatsu T, Nakai H, Masaki K, Iida S. Pharmacokinetic studies of 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) in dogs. Blood or plasma levels, metabolism and excretion after a single intravenous administration. Yakubutsu Dotai. 1996;11(5):499–504.Google Scholar
- 32.Ma L, Sun J, Peng Y, Zhang R, Shao F, Hu X, et al. Glucuronidation of edaravone by human liver and kidney microsomes: biphasic kinetics and identification of UGT1A9 as the major UDP-glucuronosyltransferase isoform. Drug Metab Dispos. 2012;40(4):734–41. https://doi.org/10.1124/dmd.111.043356.CrossRefPubMedGoogle Scholar
- 33.Le Liboux A, Lefebvre P, Le Roux Y, Truffinet P, Aubeneau M, Kirkesseli S, et al. Single- and multiple-dose pharmacokinetics of riluzole in white subjects. J Clin Pharmacol. 1997;37(9):820–7. https://doi.org/10.1002/j.1552-4604.1997.tb05630.x.CrossRefPubMedGoogle Scholar
- 34.Nakamaru Y, Kinoshita S, Kawaguchi A, Takei K, Palumbo J, Suzuki M. Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(suppl 1):80–7. https://doi.org/10.1080/21678421.2017.1353100.CrossRefPubMedGoogle Scholar
- 35.Le Liboux A, Cachia JP, Kirkesseli S, Gautier JY, Guimart C, Montay G, et al. A comparison of the pharmacokinetics and tolerability of riluzole after repeat dose administration in healthy elderly and young volunteers. J Clin Pharmacol. 1999;39(5):480–6. https://doi.org/10.1177/009127009903900507.CrossRefPubMedGoogle Scholar
- 36.RADICAVA (edaravone injection) [prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209176lbl.pdf. Accessed 22 Dec 2017.
- 39.Kaste M, Murayama S, Ford GA, Dippel DW, Walters MR. Tatlisumak T; MCI-186 study group. Safety, tolerability and pharmacokinetics of MCI-186 in patients with acute ischemic stroke: new formulation and dosing regimen. Cerebrovasc Dis. 2013;36(3):196–204. https://doi.org/10.1159/000353680.CrossRefPubMedGoogle Scholar
- 41.Takamatsu Y, Yamamoto M, Hisanaga N. Studies on the metabolic fate of MCI-186 in rats. Jpn Pharmacol Ther. 1996;24:176–81.Google Scholar
- 43.Dash RP, Jayachandra Babu R, Srinivas NR. Therapeutic potential and utility of elacridar with respect to P-glycoprotein inhibition: an insight from the published in vitro, preclinical and clinical studies. Eur J Drug Metab Pharmacokinet. 2017;42(6):915–33. https://doi.org/10.1007/s13318-017-0411-4.CrossRefPubMedGoogle Scholar
- 47.Milane A, Tortolano L, Fernandez C, Bensimon G, Meininger V, Farinotti R. Brain and plasma riluzole pharmacokinetics: effect of minocycline combination. J Pharm Sci. 2009;12(2):209–17.Google Scholar
- 48.Gutierrez J, Federici T, Peterson B, Bartus R, Betourne A, Boulis NM. Development of intrathecal riluzole: a new route of administration for the treatment of amyotrophic lateral sclerosis patients. Neurosurgery. 2016;63(Suppl 1):193. https://doi.org/10.1227/01.neu.0000489810.52605.80.CrossRefGoogle Scholar
- 57.Zhou S, Yu G, Chi L, Zhu J, Zhang W, Zhang Y, et al. Neuroprotective effects of edaravone on cognitive deficit, oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats. Neurotoxicology. 2013;38:136–45. https://doi.org/10.1016/j.neuro.2013.07.007.CrossRefPubMedGoogle Scholar
- 58.Isfahan University of Medical Sciences. Treatment effect of edaravone in patients with amyotrophic lateral sclerosis (ALS) [ClinicalTrials.gov Identifier: NCT03272802]. https://clinicaltrials.gov/ct2/show/study/NCT03272802. Accessed 22 Dec 2017.
- 59.Sato T, Mizuno K, Ishii F. A novel administration route of edaravone–II: mucosal absorption of edaravone from edaravone/hydroxypropyl-beta-cyclodextrin complex solution including l-cysteine and sodium hydrogen sulfite. Pharmacology. 2010;85(2):88–94. https://doi.org/10.1159/000276548.CrossRefPubMedGoogle Scholar
- 62.Groeneveld GJ, Van Kan HJ, Kalmijn S, Veldink JH, Guchelaar HJ, Wokke JH, et al. Riluzole serum concentrations in patients with ALS: associations with side effects and symptoms. Neurology. 2003;61(8):1141–3. https://doi.org/10.1212/01.WNL.0000090459.76784.49.CrossRefPubMedGoogle Scholar