Zonisamide

Zonisamide is a medication used to treat the symptoms of epilepsy and Parkinson's disease.[2][3] Chemically it is a sulfonamide. It serves as an anticonvulsant used primarily as an adjunctive therapy in adults with Parkinson's disease, partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic and generalized tonic clonic seizure.[4] Despite this it is also sometimes used as a monotherapy for partial-onset seizures.[3][5]

Zonisamide
Clinical data
Trade namesZonegran
AHFS/Drugs.comMonograph
MedlinePlusa603008
License data
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability~100%[1]
    Protein binding40%[1]
    MetabolismHepatic through CYP3A4[1]
    Elimination half-life63 hours in plasma[1]
    ExcretionRenal (62%); Faeces (3%)[1]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    CompTox Dashboard (EPA)
    ECHA InfoCard100.118.526
    Chemical and physical data
    FormulaC8H8N2O3S
    Molar mass212.227 g/mol g·mol−1
    3D model (JSmol)
    Melting point162 °C (324 °F)
      (verify)

    Medical uses

    Epilepsy

    Zonisamide is approved in the United States,[6] and United Kingdom[7] for adjunctive treatment of partial seizures in adults and Japan for both adjunctive and monotherapy for partial seizures (simple, complex, secondarily generalized), generalized (tonic, tonic-clonic (grand mal), and atypical absence) and combined seizures.[8] In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.[5]

    Parkinson's disease

    It has been approved for the treatment of the motor symptoms of Parkinson's disease, as an adjunct to levodopa, in a few countries such as Japan.[2][3] In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009 [9]. More recently, Murata et al published a randomised double-blind placebo controlled study that served as Class 1 evidence of zonisamide and its role in treating parkinsonian symptoms of Dementia with Lewy Bodies [10]. The study found Zonisamide did not worsen cognitive function, behavioural and psychological symptoms of dementia, or caregiver burden. The overall incidence of adverse events was higher in the zonisamide 50 mg than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%, respectively).

    Tardive dyskinesia

    In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.[11]

    Obesity

    It has also been studied for obesity[12] with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication.[13][14][15] It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.[16]

    Migraine

    Zonisamide has been studied for and used as a migraine preventative medication, when topiramate is either ineffective or cannot be continued due to side effects.[3]

    Bipolar depression

    It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[17][18]

    Adverse effects

    Adverse effects by incidence:[1][19][20]

    Very common (>10% incidence) adverse effects include:

    • Anorexia
    • Somnolence
    • Dizziness
    • Agitation
    • Irritability
    • Confusional state
    • Depression
    • Diplopia
    • Memory impairment
    • Decreased bicarbonate

    Common (1-10% incidence) adverse effects include:

    Interactions

    Zonisamide and other carbonic anhydrase inhibitors such as topiramate, furosemide, and hydrochlorothiazide have been known to interfere with amobarbital, which has led to inadequate anesthetization during the Wada test.[21] Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[1]

    Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the CYP3A4 enzyme.[22]

    Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.[23]

    Mechanism of action

    Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity).[5] It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant topiramate). It is also known to modulate GABAergic and glutamatergic neurotransmission.[5][24][25][26][27]

    Pharmacokinetics

    Absorption

    Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8-3.9 hours. Bioavailability is close to 100% and food has no effect on the bioavailability of zonisamide but may affect the rate of absorption.[28][23]

    Metabolism

    Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[29] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[30]

    History

    Zonisamide was discovered by Uno and colleagues in 1972[31] and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan.[32] It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to Eisai Co., Ltd. in 2004.[33] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[34] and Europe (starting in Germany and the United Kingdom).[35]

    References
    1. "Zonegran® Product Information" (PDF). TGA eBusiness Services. SciGen (Australia) Pty Ltd. 4 April 2013. Retrieved 18 November 2013.
    2. Grover, ND; Limaye, RP; Gokhale, DV; Patil, TR (November–December 2013). "Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease". Indian Journal of Pharmacology. 45 (6): 547–55. doi:10.4103/0253-7613.121266. PMC 3847242. PMID 24347760.
    3. Brayfield, A, ed. (8 March 2016). "Zonisamide: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 19 August 2017.
    4. Souney, P; Mutnick, A; Shargel, L (2007). Comprehensive Pharmacy Review (6th ed.). Williams & Wilkins. p. 988. ISBN 9780781765619. OCLC 869677890.CS1 maint: multiple names: authors list (link)
    5. Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
    6. Élan Pharmaceuticals Inc (22 August 2003). "NDA 20-789/S-001; Zonegran (zonisamide) Capsules 25, 50, 100 mg FDA Approvable Labeling Text" (PDF). Zonisamide Approval History. Food and Drug Administration. Retrieved 24 August 2009.
    7. Eisai Ltd. (2005). "Zonegran Summary of Product Characteristics". electronic Medicines Compendium. Medicines.org.uk. Archived from the original on 8 November 2005. Retrieved 13 November 2005.
    8. Dainippon Pharmaceutical Co., Ltd. (2004). "EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20%" (PDF). Archived from the original (PDF) on 2007-09-28. Retrieved 13 March 2006.
    9. Murata M et al. Neurology 2007; 68(1): 45-50
    10. Miho Murata et al. Adjunct zonisamide to levodopa for DLB parkinsonism. Neurology Feb 2018, 90 (8) e664-e672
    11. Iwata, Y; Irie, S; Uchida, H; Suzuki, T; Watanabe, K; Iwashita, S; Mimura, M (15 April 2012). "Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial". Journal of the Neurological Sciences. 315 (1–2): 137–140. doi:10.1016/j.jns.2011.12.010. PMID 22285275.
    12. Gadde, KM; Franciscy, DM; Wagner, II, HR; Krishnan, KRR (April 2003). "Zonisamide for Weight Loss in Obese Adults: A Randomized Controlled Trial". Journal of the American Medical Association. 289 (14): 1820–1825. doi:10.1001/jama.289.14.1820. PMID 12684361.
    13. University of Cincinnati (2005). "Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity". ClinicalTrials.gov. Retrieved 2006-05-04.
    14. Tuscaloosa Research; Education Advancement Corporation (2005). "Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial". ClinicalTrials.gov. Retrieved 2006-05-04.
    15. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2006). "Zonisamide for Weight Reduction in Obese Adults". ClinicalTrials.gov. Retrieved 2006-05-04.
    16. "Bupropion/zonisamide". AdisInsight. Springer. 20 May 2017. Retrieved 19 August 2017.
    17. Brian D. Loftus (2004). "Zonegran". Retrieved 2006-11-29.
    18. Hasegawa, H (May 2004). "utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital". Curr Med Res Opin. 20 (5): 577–580. doi:10.1185/030079904125003313. PMID 15140322.
    19. "Zonegran 25, 50, 100 mg Hard Capsules". electronic Medicines Compendium. Eisai Ltd. 8 October 2013. Retrieved 18 November 2013.
    20. "zonisamide (Rx) - Zonegran". Medscape Reference. WebMD. Retrieved 18 November 2013.
    21. Bookheimer, S; Schrader, LM; Rausch, R; Sankar, R; Engel, J (February 2005). "Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications". Epilepsia. 46 (2): 236–43. doi:10.1111/j.0013-9580.2005.23904.x. PMID 15679504.
    22. Nakasa, H; Nakamura, H; Ono, S; Tsutsui, M; Kiuchi, M; Ohmori, S; Kitada, M (April 1998). "Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data". European Journal of Clinical Pharmacology. 54 (2): 177–83. doi:10.1007/s002280050442. PMID 9626925.
    23. "Zonegran 25, 50, 100 mg Hard Capsules". Electronic Medicines Compendium (eMC). Retrieved 12 April 2017.
    24. Leppik, Ilo E. (December 2004). "Zonisamide: chemistry, mechanism of action, and pharmacokinetics". Seizure. 13 (Suppl 1): S5–9, discussion S10. doi:10.1016/j.seizure.2004.04.016. PMID 15511691.
    25. Mimaki, T; Suzuki, Y; Tagawa, T; Karasawa, T; Yabuuchi, H (March 1990). "Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain". Medical Journal of Osaka University. 39 (1–4): 13–7. PMID 1369646.
    26. Mimaki, T; Suzuki, Y; Tagawa, T; Karasawa, T; Yabuuchi, H (March 1990). "[3H]zonisamide binding in rat brain". Medical Journal of Osaka University. 39 (1–4): 19–22. PMID 1369647.
    27. Ueda, Y; Doi, T; Tokumaru, J; Willmore, J (2003-08-19). "Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures". Molecular Brain Research. 116 (1–2): 1–6. doi:10.1016/S0169-328X(03)00183-9. PMID 12941455.
    28. "Zonisamide". www.drugbank.ca.
    29. Ohmori, S; Nakasa H; Asanome K; Kurose Y; Ishii I; Hosokawa M; Kitada M (1998-05-08). "Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells". Biochimica et Biophysica Acta. 1380 (3): 297–304. doi:10.1016/s0304-4165(97)00156-6. PMID 9555064.
    30. Stiff, DD; Robicheau JT; Zemaitis MA (January 1992). "Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative". Xenobiotica. 22 (1): 1–11. doi:10.3109/00498259209053097. PMID 1615700.
    31. Shah J, Kent S, Daniel MC (2002-06-15) [1972]. "Zonisamide". In René H, Levy RH, Brian SM, Perrucca E (eds.). Antiepileptic Drugs (Fifth ed.). Philadelphia: Lippincott Williams & Wilkins. p. 873. ISBN 0-7817-2321-3. Retrieved 2007-11-07.
    32. Dainippon Sumitomo Pharma Co. Ltd. (2005). "Company History". Company Information. Dainippon Sumitomo Co., Ltd. Archived from the original on 13 February 2006. Retrieved 12 November 2005.
    33. Dainippon Pharmaceutical Co. Ltd. (2004). "Transfer of Rights Agreement for North America and Europe Reached on Zonegran". News Releases for Dainippon Pharmaceutical in 2004. Dainippon Sumitomo Pharma Co., Ltd. Archived from the original on 13 February 2006. Retrieved 12 November 2005.
    34. Dainippon Pharmaceutical Co. Ltd. (2005). "Dainippon Pharmaceutical and Eisai Conclude Agreement for the Development, Manufacture and Marketing of the Anti-Epileptic Agent Zonisamide in Asia". Dainippon Pharmaceutical News Releases for 2005. Dainippon Sumitomo Pharma Co., Ltd. Archived from the original on 22 February 2006. Retrieved 12 November 2005.
    35. Eisai Co. Ltd. (2005). "Eisai Announces Launch of Zonegran (zonisamide), Treatment For Epilepsy In the UK and Germany". Eisai 2005 News Releases. Eisai Co., Ltd. Archived from the original on 2005-10-28. Retrieved 12 November 2005.
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