Zonisamide: pharmacokinetics, efficacy, and adverse events in children with epilepsy
Karin M Wallander1, Inger Ohman2, Maria Dahlin1
1Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Insights
Young children and those on enzyme-inducing medications require higher zonisamide doses for effective treatment of refractory epilepsy. Zonisamide did not affect other antiepileptic drugs but fatigue was a common side effect.
Area of Science:
- Pediatric Neurology
- Clinical Pharmacology
Background:
- Zonisamide is a newer antiepileptic drug (AED) used for refractory epilepsy in children.
- Pediatric pharmacokinetics differ from adults, necessitating specific dosing studies.
- Previous studies were limited, leading to off-label use.
Purpose of the Study:
- To examine the pharmacokinetics, efficacy, and safety of zonisamide in children with refractory epilepsy.
- To identify factors influencing zonisamide clearance and dosing requirements.
Main Methods:
- Retrospective analysis of medical records from 75 children with pharmacoresistant epilepsy.
- Measured zonisamide clearance using the dose-to-concentration ratio.
- Extracted data on seizure reduction and adverse events.
Main Results:
- Zonisamide clearance was significantly higher in young children (0-4 years) and those on enzyme-inducing comedication (1.7-1.8 fold increases).
- No significant gender-based differences in clearance were observed.
- Overall efficacy for ≥ 50% seizure reduction was 35%; fatigue was the most common adverse event (23%).
Conclusions:
- Higher weight-normalized zonisamide doses may be needed for young children and those on enzyme-inducing comedication.
- Zonisamide does not impact the pharmacokinetics of concomitant AEDs.
- Further pharmacokinetic research in pediatric populations is essential.
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.
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