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Pharmacokinetics of Clobazam and N-Desmethylclobazam in Children with Dravet Syndrome Receiving Concomitant Stiripentol and Valproic Acid

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Abstract

Aim

The aim of this study was to describe the pharmacokinetics of clobazam and its active metabolite N-desmethylclobazam (N-CLB) in children with Dravet syndrome receiving the stiripentol/valproic acid/clobazam combination therapy of reference and to determine the concentrations of clobazam and N-CLB obtained in this population for the usual 0.2 mg/kg twice-daily dose.

Methods

Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using NONMEM® software). Four blood samples were drawn per patient. Area under the plasma concentration–time curve (AUC) and trough concentration (C trough) values for clobazam and N-CLB were simulated for 12,000 theoretical children weighing between 10 and 60 kg.

Results

The pharmacokinetics of clobazam were described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N-CLB were also first-order processes. The apparent total clearance (CL/F) and distribution volume (V CLB/F) of clobazam and the elimination rate constant of N-CLB (Kem) were related to body weight by allometric equations. Mean population estimates (% inter-individual variability) were 1.23 L/h (29 %) for CL/F, 39.1 L (18 %) for V CLB/F and 0.0706 h−1 (26 %) for Kem. The AUC values for clobazam and N-CLB were found to increase by 100 % when bodyweight increased from 10 to 60 kg, and the simulated C trough values were higher than the currently accepted target values (0.03–0.3 mg/L for clobazam and 0.3–3 mg/L for N-CLB).

Conclusion

This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children. Indicative values for the routine therapeutic drug monitoring of clobazam in children with Dravet syndrome treated by stiripentol are provided. The possible consequences of the weight-related changes on clobazam and N-CLB exposures should be further evaluated.

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Acknowledgments

This study was conducted with the financial support of Biocodex. C.C. and M.T. had support from Biocodex for the submitted work; C.C. received non-financial support from Biocodex in the previous 3 years. The other authors declare no conflict of interest. The authors have full control of all primary data and agree to allow the journal to review their data if requested.

The authors would like to thank Mireille Cammas (INSERM U1129) for her technical participation in drug assay.

Ethical standards

This study was a part of the ‘STIPOP’ study (EUDRACT Number: 2007-001784-30) and was approved by the local Ethic Committee (CPP Île de France III, reference number: 2435). Parents of all children had to provide a written informed consent as well as the child if he/she was able to understand the study procedure.

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Authors and Affiliations

  1. Inserm U1129, Paris, France

    Vincent Jullien, Stéphanie Chhun, Elisabeth Rey, Olivier Dulac, Catherine Chiron & Gérard Pons

  2. Université Paris Descartes, Paris, France

    Vincent Jullien, Stéphanie Chhun, Elisabeth Rey, Olivier Dulac, Catherine Chiron & Gérard Pons

  3. CEA, Gif-sur-Yvette, France

    Vincent Jullien, Stéphanie Chhun, Elisabeth Rey, Olivier Dulac, Catherine Chiron & Gérard Pons

  4. Service de Pharmacologie, Hôpital européen Georges Pompidou, 20 rue Leblanc, 75015, Paris, France

    Vincent Jullien

  5. Service d’Immunologie Biologique, Groupe Hospitalier Necker-Enfants Malades, Paris, France

    Stéphanie Chhun

  6. APHP, Service de Neuropédiatrie, Groupe Hospitalier Necker-Enfants Malades, Paris, France

    Olivier Dulac

  7. Département de Physiologie-Pharmacologie-Toxicologie, Faculté de Pharmacie, Université Lyon I, Lyon, France

    Michel Tod

Authors
  1. Vincent Jullien
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  2. Stéphanie Chhun
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  3. Elisabeth Rey
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  4. Olivier Dulac
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  5. Michel Tod
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  6. Catherine Chiron
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  7. Gérard Pons
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Correspondence to Vincent Jullien.

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Jullien, V., Chhun, S., Rey, E. et al. Pharmacokinetics of Clobazam and N-Desmethylclobazam in Children with Dravet Syndrome Receiving Concomitant Stiripentol and Valproic Acid. Clin Pharmacokinet 54, 527–536 (2015). https://doi.org/10.1007/s40262-014-0223-5

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  • DOI: https://doi.org/10.1007/s40262-014-0223-5

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