Related Experiment Video
Updated: Aug 6, 2026
Electrophoretic Delivery of γ-aminobutyric Acid (GABA) into Epileptic Focus Prevents Seizures in Mice
Published on: May 16, 2019
Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover
José L Herranz1, Rosa Arteaga, Javier Adín
1Neuropediatric Service, Marqués de Valdecilla University Hospital, University of Cantabria School of Medicine, Avenida de Valdecilla s/n, 39008, Santander, Spain.
Insights
Sustained-release valproate (VPA) showed similar efficacy and tolerability to conventional VPA in children with epilepsy. Once-daily evening dosing (ChVoe) was preferred by patients and parents.
Area of Science:
- Pediatric Neurology
- Pharmacology
- Epilepsy Treatment
Background:
- Conventional valproate (VPA) formulations may have compliance issues and serum concentration fluctuations.
- Sustained-release VPA formulations are hypothesized to improve tolerability and efficacy.
- Comparative trials in children are limited.
Purpose of the Study:
- To compare the efficacy, tolerability, and patient preference of conventional VPA twice daily (CVbid) versus sustained-release chrono VPA (ChVPA) administered twice daily (ChVbid), once daily in the morning (ChVom), or once daily in the evening (ChVoe) in children.
- To evaluate VPA pharmacokinetics across different administration regimens.
Main Methods:
- A randomized crossover trial involving 48 children (aged 5-14 years) with newly diagnosed partial or idiopathic generalized epilepsy.
- Four 4-month phases, comparing CVbid, ChVbid, ChVom, and ChVoe in monotherapy.
- VPA serum concentrations and pharmacokinetic data were analyzed.
Main Results:
- No significant differences in seizure control efficacy (73-83%) or adverse reaction frequency (46-67%) were observed between regimens.
- Patient/parent preference significantly favored once-daily evening dosing: ChVoe (31%) > ChVom (25%) > CVbid (17%) > ChVbid (8%).
- VPA serum concentration fluctuations varied, with higher fluctuations noted for ChVom compared to CVbid or ChVbid.
Conclusions:
- Chrono valproate (ChVPA) demonstrates comparable efficacy and tolerability to conventional valproate (VPA) in pediatric epilepsy.
- The primary benefit of chrono valproate lies in its once-daily administration, particularly in the evening, improving patient preference.
- Further confirmation with larger studies is recommended.
Objective:
It has been suggested that sustained-release valproate (VPA) formulations may be more effective and better tolerated than conventional VPA due to better compliance and lower fluctuations in VPA serum concentrations, but comparative trials with conventional VPA in children are scarce. This randomized and crossover trial compared the efficacy (complete control of seizures), the tolerability, and the patient (or parents) preference of conventional VPA twice daily (CVbid) with those of sustained-release chrono VPA twice daily (ChVbid), once daily in the morning (ChVom) or once daily in the evening (ChVoe) in monotherapy.
Methods:
The study was carried out in 48 children (29 girls), aged 5-14 years, with newly diagnosed partial epilepsy (n=26), or idiopathic generalized epilepsy (n=22). The study duration was 16 months (four phases of 4 months each). VPA pharmacokinetics data were also compared in the different regimens. Mean VPA dosage was of approximately 870 mg/day (approximately 22 mg/kg/day) and mean VPA concentration was of approximately 89 mg/l at 12 h post-dose and of 54 mg/l at 24 h post-dose.
Results:
By intention in treatment there were no significant differences in efficacy (73%, 83%, 77% and 75%, respectively) or in adverse reaction frequency (56%, 58%, 67% and 46%, respectively). There were significant differences, however, in patient (or parents) preference, the order being ChVoe (31%) > ChVom (25%) > CVbid (17%) > ChVbid (8%). The mean VPA serum concentration fluctuation between 4 h and 0 h post-morning-dose was nonsignificantly lower after CVbid than after ChVbid. Fluctuation was significantly higher after ChVom than after CVbid or ChVbid. The mean VPA serum concentration difference between 12 h and 24 h post-dose was approximately 40 mg/l.
Conclusion:
Although our results should be confirmed by a larger study, they suggest that the efficacy and tolerability of chrono valproate is similar to that of conventional valproate, and that the main advantage is the once-daily administration.
Related Concept Videos
01:20Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism
01:23Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption
01:17Pharmacokinetics in Pediatric Patients: Drug Distribution
01:20Antiepileptic Drugs: Potassium Channel Activators
Ezogabine has gained approval as an adjunctive treatment...
01:26Pharmacokinetics in Pediatric Patients: Drug Excretion