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Clin Pharmacokinet. 2018 Jun;57(6):739-748. doi: 10.1007/s40262-017-0592-7.

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

Peigné S1,2,3, Chhun S1,2,3, Tod M4,5, Rey E1,2,3, Rodrigues C1,2,3, Chiron C1,2,3, Pons G1,2,3, Jullien V6,7,8,9,10.

Author information

1
INSERM U1129, Paris, France.
2
Paris Descartes University, PRES Sorbonne Paris Cité, Paris, France.
3
CEA, Gif sur Yvette, France.
4
Département de Physiologie-Pharmacologie-Toxicologie, Faculté de Pharmacie, Université Lyon I, Lyon, France.
5
Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
6
INSERM U1129, Paris, France. vincent.jullien@aphp.fr.
7
Paris Descartes University, PRES Sorbonne Paris Cité, Paris, France. vincent.jullien@aphp.fr.
8
CEA, Gif sur Yvette, France. vincent.jullien@aphp.fr.
9
Service de Pharmacologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015, Paris, France. vincent.jullien@aphp.fr.
10
Assistance Publique-Hôpitaux de Paris, Paris, France. vincent.jullien@aphp.fr.

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).

PMID:
28819726
DOI:
10.1007/s40262-017-0592-7

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