European Journal of Clinical Pharmacology

, Volume 74, Issue 6, pp 793–803 | Cite as

A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy

  • Christelle Rodrigues
  • Stéphanie Chhun
  • Catherine Chiron
  • Olivier Dulac
  • Elisabeth Rey
  • Gérard Pons
  • Vincent Jullien
Pharmacokinetics and Disposition



The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50–100 mg/L).


Ninety-eight children (1–17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg.


A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%.


If the present study supports the current dose recommendations of 20–30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.


Childhood epilepsy Valproate Population pharmacokinetics Protein binding 



The authors would like to thank Dr. Mathilde Chipaux (Fondation Ophtalmologic Rothschild) for her participation in patient inclusion of the VAPOP study.

Authors’ contribution

CR drafted the original manuscript; CR and VJ performed the PK modelling analysis; SC and ER realized the analytical dosages; SC, CC, OD, ER, GP and VJ conceptualized the study and revised the manuscript.


Study 1 (VAPOP) was funded by Sanofi Aventis France (registration NCT00385411) and study 2 (STIPOP) was funded by Biocodex (EudraCT number: 2007–001784-30). The present work was returned independently from Biocodex.

Compliance with ethical standards

Conflicts of interest

CR reports personal fees from Biocodex, outside the submitted work. CC reports personal fees and non-financial support from Biocodex; personal fees from Brabant, UCB-Pharma, Bial, Zogenix, and Viropharma, outside the submitted work; and declare that she was the PI of the two clinical studies mentioned in the paper. As clinical principal investigator, CC recruited and followed the patients during the studies. That did not influence what is written in the submitted work. VJ, SC, ER, GP, and OD have nothing to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

228_2018_2444_MOESM1_ESM.docx (2 mb)
ESM 1 (DOCX 2024 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Christelle Rodrigues
    • 1
  • Stéphanie Chhun
    • 2
  • Catherine Chiron
    • 1
  • Olivier Dulac
    • 1
  • Elisabeth Rey
    • 1
  • Gérard Pons
    • 1
  • Vincent Jullien
    • 1
    • 3
  1. 1.INSERM U1129Paris Descartes UniversityParisFrance
  2. 2.Hôpital Necker-Enfants Malades – Enfants Malades, Inserm U1151, INEM, Laboratoire d’immunologie biologiqueAssistance Publique – Hôpitaux de ParisParisFrance
  3. 3.Service de PharmacologieHôpital Européen Georges PompidouParisFrance

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