Zonisamide: Pharmacokinetics, Efficacy, and Adverse Events in Children with Epilepsy

Abstract

Background Zonisamide is a new generation antiepileptic drug (AED) widely used in children with refractory epilepsy, although until recently, it was used to a large extent as off-label or unlicensed medication due to the lack of evidence-based studies. Children have a different pharmacokinetic profile than adults and an adult dose regimen cannot be directly translated into pediatric use.

Patients and Methods In this retrospective noninterventional study of the medical records of 75 children with pharmacoresistant epilepsy, the pharmacokinetics, efficacy and safety of zonisamide were examined. The dose-to-concentration ratio, the daily weight-normalized dose of zonisamide divided by its plasma concentration, was used as a measure of clearance. In addition, data on the efficacy of zonisamide to reduce seizures and reported adverse events were extracted from the medical records and analyzed.

Results Young children (range, 0–4 years) had a significantly increased zonisamide clearance compared with older ones (range, 5–17 years) and those with enzyme-inducing comedication (carbamazepine, phenobarbital, or phenytoin) had increased clearance compared with those on nonenzyme inducers; the increases were 1.7-fold and 1.8-fold, respectively. No significant difference in clearance was found between female and male subjects. The clearances of concomitant AEDs were not affected by zonisamide administration. The overall efficacy of zonisamide for reducing seizure frequency ≥50% was 35% and the most frequent adverse event was fatigue, reported in 23% of the patients.

Conclusion Patients with enzyme-inducing comedication or of young age (range, 0–4 years) might need higher weight-normalized doses to achieve the same plasma levels as in patients with no enzyme-inducing comedication or patients of older age. Zonisamide was not found to influence the pharmacokinetics of concomitant AEDs. The shortage of pharmacokinetic studies of zonisamide in children highlights the need for research of this kind.

Keywords

zonisamide - pharmacokinetics - children - age - comedication

• References

• 1 European Medicines Agency–Zonegran . Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000577/human_med_001183.jsp&mid=WC0b01ac058001d124 . Accessed on December 24, 2013
• 2 Holder Jr JL, Wilfong AA. Zonisamide in the treatment of epilepsy. Expert Opin Pharmacother 2011; 12 (16) 2573-2581
• 3 Hashimoto Y, Odani A, Tanigawara Y, Yasuhara M, Okuno T, Hori R. Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients. Biol Pharm Bull 1994; 17 (2) 323-326
• 4 Ojemann LM, Shastri RA, Wilensky AJ , et al. Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy. Ther Drug Monit 1986; 8 (3) 293-296
• 5 Shinoda M, Akita M, Hasegawa M, Hasegawa T, Nabeshima T. The necessity of adjusting the dosage of zonisamide when coadministered with other anti-epileptic drugs. Biol Pharm Bull 1996; 19 (8) 1090-1092
• 6 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 (11) 1230-1234
• 7 Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia 2007; 48 (3) 435-441
• 8 Miura H. Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies. Seizure 2004; 13 (Suppl. 01) S17-S23 , discussion S24–S25
• 9 Conroy S, Choonara I, Impicciatore P , et al; European Network for Drug Investigation in Children. Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ 2000; 320 (7227) 79-82
• 10 Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003; 2 (6) 347-356
• 11 European Medicines Agency–Paediatric medicine–Paediatric Regulation. . Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsp&mid=WC0b01ac0580025b8b . Accessed: December 24, 2013
• 12 Weintraub D, Buchsbaum R, Resor Jr SR, Hirsch LJ. Effect of antiepileptic drug comedication on lamotrigine clearance. Arch Neurol 2005; 62 (9) 1432-1436
• 13 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) 1-11
• 14 Fukuoka N, Tsukamoto T, Uno J, Kimura M, Morita S. Influence of coadministered antiepileptic drugs on serum zonisamide concentrations in epileptic patients: quantitative analysis based on suitable transforming factor. Biol Pharm Bull 2003; 26 (12) 1734-1738
• 15 Okada Y, Seo T, Ishitsu T , et al. Population estimation regarding the effects of cytochrome P450 2C19 and 3A5 polymorphisms on zonisamide clearance. Ther Drug Monit 2008; 30 (4) 540-543
• 16 Ragueneau-Majlessi I, Levy RH, Brodie M, Smith D, Shah J, Grundy JS. Lack of pharmacokinetic interactions between steady-state zonisamide and valproic acid in patients with epilepsy. Clin Pharmacokinet 2005; 44 (5) 517-523
• 17 Levy RH, Ragueneau-Majlessi I, Brodie MJ, Smith DF, Shah J, Pan W-J. Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy. Ther Drug Monit 2005; 27 (2) 193-198
• 18 Guerrini R, Rosati A, Segieth J, Pellacani S, Bradshaw K, Giorgi L. A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy. Epilepsia 2013; 54 (8) 1473-1480
• 19 Glauser TA, Pellock JM. Zonisamide in pediatric epilepsy: review of the Japanese experience. J Child Neurol 2002; 17 (2) 87-96
• 20 Seki T, Kumagai N, Maezawa M. Effects of zonisamide monotherapy in children with epilepsy. Seizure 2004; 13 (Suppl. 01) S26-S32 , discussion S33
• 21 Shinnar S, Pellock JM, Conry JA. Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol 2009; 13 (1) 3-9