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Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover study comparing clinical effects, patient preference and pharmacokinetics

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Abstract

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.

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Acknowledgements

The study was performed with informed consent and following all the guidelines for experimental investigation with human subjects required by the Drug Spanish Agency, as well as the Helsinki Declaration of 1975 as revised in 1996. The protocol of this randomized, comparative and crossover phase IV clinical trial was approved by the Ethics Committee of the Marques de Valdecilla University Hospital and the Drug Spanish Agency.

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Authors and Affiliations

  1. Neuropediatric Service, Marqués de Valdecilla University Hospital, University of Cantabria School of Medicine, Avenida de Valdecilla s/n, 39008, Santander, Spain

    José L. Herranz & Rosa Arteaga

  2. Clinical Pharmacology Service, Marqués de Valdecilla University Hospital, University of Cantabria School of Medicine, Avenida de Valdecilla s/n, 39008, Santander, Spain

    Javier Adín & Juan A. Armijo

Authors
  1. José L. Herranz
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  2. Rosa Arteaga
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  3. Javier Adín
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  4. Juan A. Armijo
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Correspondence to Juan A. Armijo.

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Herranz, J.L., Arteaga, R., Adín, J. et al. Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover study comparing clinical effects, patient preference and pharmacokinetics. Eur J Clin Pharmacol 62, 805–815 (2006). https://doi.org/10.1007/s00228-006-0175-2

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  • DOI: https://doi.org/10.1007/s00228-006-0175-2

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