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Population Pharmacokinetics of Stiripentol in Paediatric Patients with Dravet Syndrome Treated with Stiripentol, Valproate and Clobazam Combination Therapy

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Abstract

Aim

The aim of this study was to describe the pharmacokinetics of stiripentol in children with Dravet syndrome and to determine the concentrations of stiripentol achieved in this population for the usual 25 mg/kg twice-daily dose.

Methods

Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using MONOLIX software). Four blood samples were drawn per patient. Stiripentol area under the plasma concentration–time curve (AUC) values and trough concentrations were simulated for 7000 theoretical children weighing between 10 and 70 kg for the 25 mg/kg twice-daily dose.

Results

The pharmacokinetics of stiripentol was described using a one-compartment model with zero-order absorption and first-order elimination. The apparent clearance (CL/F) and apparent volume of distribution (V d/F) of stiripentol were related to body weight by allometric equations. A dose-dependent non-linearity was also observed with an allometric model relating CL/F to the weight-normalised dose. Mean population estimates (% inter-individual variability) were 4.2 L/h (21%) for CL/F and 82 L (25%) for V d/F. The AUC of stiripentol increased by 300% when body weight increased from 10 to 70 kg.

Conclusion

This population pharmacokinetic model of stiripentol in children with Dravet syndrome confirmed the dose-dependent non-linearity that has been evidenced in adults. It also supported that a 25 mg/kg twice-daily dose might lead to excessive exposure in children >30 kg, suggesting an eventual dose adjustment during adolescence.

Clinical Trial Identifier

This study is part of the STIPOP study (EUDRACT number: 2007-001784-30).

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Acknowledgements

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

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Authors and Affiliations

  1. INSERM U1129, Paris, France

    Sophie Peigné, Stéphanie Chhun, Elisabeth Rey, Christelle Rodrigues, Catherine Chiron, Gérard Pons & Vincent Jullien

  2. Paris Descartes University, PRES Sorbonne Paris Cité, Paris, France

    Sophie Peigné, Stéphanie Chhun, Elisabeth Rey, Christelle Rodrigues, Catherine Chiron, Gérard Pons & Vincent Jullien

  3. CEA, Gif sur Yvette, France

    Sophie Peigné, Stéphanie Chhun, Elisabeth Rey, Christelle Rodrigues, Catherine Chiron, Gérard Pons & Vincent Jullien

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

    Michel Tod

  5. Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France

    Michel Tod

  6. Service de Pharmacologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015, Paris, France

    Vincent Jullien

  7. Assistance Publique-Hôpitaux de Paris, Paris, France

    Vincent Jullien

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  1. Sophie Peigné
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  2. Stéphanie Chhun
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  3. Michel Tod
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  4. Elisabeth Rey
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  6. Catherine Chiron
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  8. Vincent Jullien
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Corresponding author

Correspondence to Vincent Jullien.

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Funding

This study was conducted with the financial support of Biocodex.

Conflict of interest

Catherine Chiron and Michel Tod had support from Biocodex for the submitted work and Catherine Chiron was PI of the clinical pharmacokinetic study; Catherine Chiron has received financial support from Biocodex in the previous 3 years. Christelle Rodrigues received a financial support from Biocodex for work not related to this study. Sophie Peigné, Stéphanie Chhun, Elisabeth Rey, Gérard Pons and Vincent Jullien declare no conflicts of interest that might be relevant to this work. The authors have full control of all primary data and agree to allow the journal to review their data if requested.

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Peigné, S., Chhun, S., Tod, M. et al. Population Pharmacokinetics of Stiripentol in Paediatric Patients with Dravet Syndrome Treated with Stiripentol, Valproate and Clobazam Combination Therapy. Clin Pharmacokinet 57, 739–748 (2018). https://doi.org/10.1007/s40262-017-0592-7

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  • DOI: https://doi.org/10.1007/s40262-017-0592-7

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