Chapter 53
Zonisamide
Book Editor(s):Simon Shorvon MA MB BChir MD FRCP,
Emilio Perucca MD PhD FRCP(Edin),
Jerome Engel Jr. MD PhD,
Simon Shorvon MA MB BChir MD FRCP
Professor in Clinical Neurology and Consultant Neurologist
UCL Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, London, UK
Search for more papers by this authorEmilio Perucca MD PhD FRCP(Edin)
Professor of Medical Pharmacology and Director, Clinical Trial Center
Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics University of Pavia, C. Mondino National Neurological Institute Pavia, Italy
Search for more papers by this authorJerome Engel Jr. MD PhD
Jonathan Sinay Distinguished Professor of Neurology and Director UCLA Seizure Disorder Center
Neurobiology, and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, USA
Search for more papers by this authorFirst published: 02 October 2015
Summary
Zonisamide was licensed as add-on therapy for focal seizures in adults in the USA in 2000 and in the EU in 2005. Zonisamide is effective in several experimental models of seizures and epilepsy. A mechanism of action similar to that of phenytoin is suggested by its activity against maximum electroshock (MES) seizures and its ability to inhibit sustained repetitive action potential firing in cultured spinal cord neurons at clinically relevant concentrations. Information on the pharmacokinetics of zonisamide in special groups is limited. Zonisamide has no clinically relevant effects on the pharmacokinetics of other commonly used AEDs. Although serum zonisamide concentrations can be measured by enzyme-linked immunoassay or high-performance liquid chromatography, the relationship between serum concentrations and efficacy is not sufficiently characterized to recommend extensive monitoring in routine clinical practice. It is an antiepileptic drug, which can be useful for the mono- and adjunctive therapy of focal epilepsies.
References
- Masuda Y, Karasawa T, Shiraishi Y, et al. 3-Sulfamoylmethyl-1,2-benzisoxazole, a new type of anticonvulsant drug: pharmacological profile. Arzneimittelforschung 1980; 30: 477–483.
- Masuda Y, Utsui Y, Shiraishi Y, et al. Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or neurotoxic effects in experimental animals. Epilepsia 1979; 20: 623–633.
- Rock DM, Macdonald RL, Taylor CP. Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD 810, CI 912), a novel anticonvulsant. Epilepsy Res 1989; 3: 138–143.
- Schauf CL. Zonisamide enhances slow sodium inactivation in Myxicola. Brain Res 1987; 413: 185–188.
- White HS. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 1999; 40(Suppl. 5): S2–S10.
- Takano K, Tanaka T, Fujita T, et al. Zonisamide: electrophysiological and metabolic changes in kainic acid-induced limbic seizures in rats. Epilepsia 1995; 36: 644–648.
- Ito T, Hori M, Masuda Y, et al. 3-Sulfamoylmethyl-1,2-benzisoxazole, a new type of anticonvulsant drug: electroencephalographic profile. Arzneimittelforschung 1980; 30: 603–609.
- Wada Y, Hasegawa H, Okuda H, Yamaguchi N. Anticonvulsant effects of zonisamide and phenytoin on seizure activity of the feline visual cortex. Brain Dev 1990; 12: 206–210.
- Ito T, Hori M, Kadokawa T. Effects of zonisamide (AD-810) on tungstic acid gel-induced thalamic generalized seizures and conjugated estrogen-induced cortical spike–wave discharges in cats. Epilepsia 1986; 27: 367–374.
- Wada Y, Hasegawa H, Yamaguchi N. Effect of a novel anticonvulsant, zonisamide (AD-810, CI-912), in an experimental model of photosensitive epilepsy. Epilepsy Res 1990; 7: 117–120.
- Bartoszyk GD, Hamer M. The genetic animal model of reflex epilepsy in the Mongolian gerbil: differential efficacy of new anticonvulsive drugs and prototype antiepileptics. Pharmacol Res Commun 1987; 19: 429–440.
- Kito M, Maehara M, Watanabe K. Mechanisms of T-type calcium channel blockade by zonisamide. Seizure 1996; 5: 115–119.
- Suzuki S, Kawakami K, Nishimura S, et al. Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex. Epilepsy Res 1992; 12: 21–27.
- Mimaki T, Suzuki Y, Tagawa T, et al. [3H]zonisamide binding in rat brain. Med J Osaka Univ 1990; 39: 19–22.
- Kawai M, Hiramatsu M, Endo A, et al. Effect of zonisamide on release of aspartic acid and gamma-aminobutyric acid from hippocampal slices of E1 mice. Neurosciences 1994; 20: 115–119.
- Okada M, Kawata Y, Mizuno K, et al.. Interaction between Ca2+, K+, carbamazepine and zonisamide on hippocampal extracellular glutamate monitored with a microdialysis electrode. Br J Pharmacol 1998; 124: 1277–1285.
- Okada M, Kaneko S, Hirano T, et al. Effects of zonisamide on dopaminergic system. Epilepsy Res 1995; 22: 193–205.
- Okada M, Hirano T, Kawata Y, et al. Biphasic effects of zonisamide on serotonergic system in rat hippocampus. Epilepsy Res 1999; 34: 187–197.
- Taylor CP, McLean JR, Brockbrader HN. Zonisamide (AD-810). In: BS Meldrum, RL Porter (eds). New Anticonvulsant Drugs. London: John Libbey, 1986: 277–294.
- Eisai Pharmaceuticals Inc. Zonegran (prescribing information). Teaneck, NJ: Eisai Pharmaceuticals Inc., 2004.
- Matsumoto K, Miyazaki H, Fujii T, et al. Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benziosoxazole (AD-810) in rats, dogs and monkeys and of AD-810 in men. Arzneimittelforschung 1983; 33: 961–968.
- Matsumoto K, Miyazaki H, Fujii T, et al. Binding of sulfonamides to erythrocyte proteins and possible drug–drug interaction. Chem Pharm Bull Tokyo 1989; 37: 2807–2810.
- Matsumoto K, Miyazaki H, Fujii T, Hashimoto M. Binding of sulfonamides to erythrocytes and their components. Chem Pharm Bull Tokyo 1989; 37: 1913–1915.
- Wagner JG, Sackellares JC, Donofrio PD, et al. Nonlinear pharmacokinetics of CI-912 in adult epileptic patients. Ther Drug Monit 1984; 6: 277–283.
- Peters DH, Sorkin EM. Zonisamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 1993; 45: 760–787.
- Faught E, Ayala R, Montouris GG, Leppik IE. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology 2001; 57: 1774–1779.
- Kochak GM, Page JG, Buchanan RA, et al. Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures. J Clin Pharmacol 1998; 38: 166–171.
- Perucca E. Clinical pharmacokinetics of new-generation anti-epileptic drugs at the extremes of age. Clin Pharmacokin 2006; 45: 351–363.
- Nakasa H, Komiya M, Ohmori S, et al. Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide. Mol Pharmacol 1993; 44: 216–221.
- Ito T, Yamaguchi T, Miyazaki H, et al. Pharmacokinetic studies of AD-810, a new antiepileptic compound. Phase I trials. Arzneimittelforschung 1982; 32: 1581–1586.
- Eisai Ltd, London, UK. Zonegran capsules. Summary of product characteristics, https://www.medicines.org.uk/emc/medicine/16240 (accessed 22 May 2015).
- Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996; 31: 29–46.
- Ragueneau-Majlessi I, Levy RH, Bergen D, et al. Carbamazepine pharmacokinetics are not affected by zonisamide: in vitro mechanistic study and in vivo clinical study in epileptic patients. Epilepsy Res 2004; 62: 1–11.
- Ragueneau-Majlessi I, Levy RH, et al. Lack of pharmacokinetic interactions between steady-state zonisamide and valproic acid in patients with epilepsy. Clin Pharmacokinet 2005; 44: 517–523.
- Levy RH, Ragueneau-Majlessi I, Garnett WR, et al. Lack of a clinically significant effect of zonisamide on phenytoin steady-state pharmacokinetics in patients with epilepsy. J Clin Pharmacol 2004; 44: 1230–1234.
- Levy RH, Ragueneau-Majlessi I, Brodie MJ, et al. Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy. Ther Drug Monit 2005; 27: 193–198.
- Griffith SG, Dai Y. Effect of zonisamide on the pharma-cokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women. Clin Ther 2004; 26: 2056–2065.
- Mather GG, Shah J. Zonisamide. Drug interactions. In: RH Levy, RH Mattson, BS Meldrum, E Perucca (eds). Antiepileptic Drugs. Philadelphia, PA: Lippincott, Williams & Wilkins, 2002: 880–884.
- Groves L, Wallace J, Shellenberger K. Effect of cimetidine on zonisamide pharmacokinetics in healthy volunteers. Epilepsia 1998; 39(Suppl. 6): 191.
- Wroe S. Zonisamide and renal calculi in patients with epilepsy: how big an issue? Curr Med Res Opin 2007; 23: 1765–1773.
- Juergens U. Simultaneous determination of zonisamide and nine other anti-epileptic drugs and metabolites in serum: a comparison of microbore and conventional high-performance liquid chromatography. J Chromatogr 1987; 385: 233–240.
- Perucca E. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin Pharmacokinet 2000; 38: 191–204.
- Sackellares JC, Ramsay RE, Wilder BJ, et al. Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures. Epilepsia 2004; 45: 610–617.
- Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993; 15: 67–73.
- Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs – best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008; 49: 1239–1276.
- Brodie MJ, Duncan R, Vespignani H, et al. Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures. Epilepsia 2005; 46: 31–41.
- Brodie MJ. Zonisamide as adjunctive therapy for refractory partial seizures. Epilepsy Res 2006; 68(Suppl. 2): S11–S16.
- Baulac M, Brodie MJ, Patten A, et al. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012; 11: 579–588.
- Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE Subcommission on AE Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54: 551–563.
- Guerrini R, Rosati A, Segieth J, et al. A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy. Epilepsia 2013; 54: 1473–1480.
- Cross JH, Auvin S, Patten A, Giorgi L. Safety and tolerability of zonisamide in paediatric patients with epilepsy. Eur J Paediatr Neurol 2014; 18: 747–758.
- Kothare SV, Valencia I, Khurana DS, et al. Efficacy and tolerability of zonisamide in juvenile myoclonic epilepsy. Epileptic Disord 2004; 6: 267–270.
- O'Rourke D, Flynn C, White M, et al. Potential efficacy of zonisamide in refractory juvenile myoclonic epilepsy: retrospective evidence from an Irish compassionate-use case series. Ir Med J 2007; 100: 431–433.
- Szaflarski JP. Effects of zonisamide on the electroencephalogram of a patient with juvenile myoclonic epilepsy. Epilepsy Behav 2004; 5: 1024–1026.
- Vossler DG, Conry JA, Murphy JV. Zonisamide for the treatment of myoclonic seizures in progressive myoclonic epilepsy: an open-label study. Epileptic Disord 2008; 10: 31–34.
- Kyllerman M, Ben Menachem E. Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients. Epilepsy Res 1998; 29: 109–114.
- Ohtahara S. Zonisamide in the management of epilepsy: Japanese experience. Epilepsy Res 2006; 68(Suppl. 2): S25–S33.
- Yamauchi T, Aikawa H. Efficacy of zonisamide: our experience. Seizure 2004; 13(Suppl. 1): S41–S48.
- Yagi K, Seino M. Methodological requirements for clinical trials in refractory epilepsies: our experience with zonisamide. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16: 79–85.
- Leppik IE. Practical prescribing and long-term efficacy and safety of zonisamide. Epilepsy Res 2006; 68(Suppl. 2): S17–S24.
- Baulac M, Leppik IE. Efficacy and safety of adjunctive zonisamide therapy for refractory partial seizures. Epilepsy Res 2007; 75: 75–83.
- Wroe SJ, Yeates AB, Marshall A. Long-term safety and efficacy of zonisamide in patients with refractory partial-onset epilepsy. Acta Neurol Scand 2008; 118: 87–93.
- Knudsen JF, Thambi LR, Kapcala LP, Racoosin JA. Oligohydrosis and fever in pediatric patients treated with zonisamide. Pediatr Neurol 2003; 28: 184–189.
- Low PA, James S, Peschel T, et al. Zonisamide and associated oligohidrosis and hyperthermia. Epilepsy Res 2004; 62: 27–34.
- Terada Y, Satoh K, Funabashi H. Reproduction studies of zonisamide (2). Teratogenicity study in rats (Cesarean section and natural delivery studies). Jpn Pharmacol Ther 1987; 15: 4399–4416.
- Terada Y, Fukagawa S, Shigematsu K. Reproduction studies of zonisamide (3). Teratogenicity study in mice, dogs, and monkeys. Jpn Pharmacol Ther 1987; 15: 4435–4453.
- Kondo T, Kaneko S, Amano Y, Egawa I. Preliminary report on teratogenic effects of zonisamide in the offspring of treated women with epilepsy. Epilepsia 1996; 37: 1242–1244.
- EURAP interim report 2014. http://www.lareb.nl/getmedia/c0de9ab6-324c-468d-b049-e62e6551cf6f/Eurap Report_Nov_2013.pdf (accessed 22 May 2015).
