Tropical Review: Zonisamide in Pediatric Epilepsy: Review of the Japanese Experience

Abstract

Zonisamide is a novel anticonvulsant that is structurally and mechanistically unique, compared with other antiepilepsy drugs. Available in Japan and South Korea since 1989, it was approved in the United States in the year 2000 as adjunctive therapy for partial seizures in adults. There has been extensive clinical trial and clinical practice experience with zonisamide therapy in Japanese children. Open-label data from pediatric clinical trials conducted in Japan suggest that zonisamide is well tolerated and effective against partial- and generalized-onset seizures in children. Despite this wealth of open-label data, no formal pharmacokinetic studies and only one well-controlled trial of zonisamide's efficacy and safety in Japanese children have been completed to date. No controlled clinical trials of zonisamide in children have been completed in the United States or Europe. Additional controlled trials in children with partial- or generalized-onset seizures, infantile spasms, and Lennox-Gastaut syndrome are warranted to further delineate zonisamide's broad spectrum of efficacy and tolerability in children.

Recent Advances in the Pharmacotherapy of Infantile Spasms

“…There are some Class IV studies of topiramate [80][81][82], valproic acid [83,84], Class I of sulthiame [85] and Class IV of zonisamide [86][87][88][89], pyridoxine [90,91], nitrazepam [92], levetiracetam [93], lamotrigine [94] and a ketogenic diet [95,96]. Topiramate is a popular second-line treatment of infantile spasms and is often used as first-line treatment, especially where there is no access to vigabatrin [74] (Class IV).…”

“…Spasm cessation was seen in 4/11 patients using doses up to 10 mg/kg/day [86] (Class IV) and in 9/27 patients with doses up to 20 mg/kg/ day [87] (Class IV). Adverse effects are similar to topiramate and include drowsiness, ataxia, gastrointestinal symptoms, oligohydrosis and renal calculi [88,89].…”

Zonisamide in the treatment of epilepsy

“…In particular, efficacy has been shown in focal epilepsies [78], IGEs (see above), in LandauKleffner syndrome [79], Dravet syndrome [80], Ohtahara syndrome [81,82], West syndrome [35, [83][84][85][86], and in Lennox Gastaut syndrome [35,[87][88][89], both in monotherapy and in adjunctive therapy.…”

Zonisamide – An Overview

“…[23][24][25] Zonisamide is distributed relatively evenly throughout the whole body; the apparent volume of distribution is 1.45 L/kg following a 400mg oral dose [5] .The drug is not highly bound to plasma proteins (40-60%).However, zonisamide has a high affinity for erythrocytes, with concentrations in these cells exceeding those in plasma by 4-to 9-fold in healthy volunteers in Japan. [7,18] Zonisamide undergoes hepatic metabolism and is primary route of excretion is by the kidneys. [5] After oral administration, inactive zonisamide metabolites identified in the urine, but not in the plasma, include N-acetyl-zonisamide and the glucuronide conjugate of the open isoxazole ring metabolite 2-sulphamoylacetyl phenol (SMAP).…”

“…[5] After oral administration, inactive zonisamide metabolites identified in the urine, but not in the plasma, include N-acetyl-zonisamide and the glucuronide conjugate of the open isoxazole ring metabolite 2-sulphamoylacetyl phenol (SMAP). Acetylation of zonisamide is mediated by N-acetyltransferase, [9] while reduction to SMAP is mediated by the cytochrome P450 isoenzyme 3A4. [5] Zonisamide has a long terminal elimination half-life (50-68 hours in plasma and 105 hours in erythrocytes) after administration of single oral 200-800mg doses in healthy volunteers in Japan and/or the US .Overall, 62% of the administered dose was recovered in the urine and 3% in the faeces.…”