title: Reassessment of stiripentol pharmacokinetics in healthy adult volunteers.
abstract: Because children who have been receiving stiripentol for the treatment of Dravet syndrome for more than 10 years are now becoming young adults, it is important to accurately characterize stiripentol pharmacokinetics in this age range. A double-blind placebo-controlled dose ranging study was therefore conducted to investigate the pharmacokinetics and tolerability of stiripentol in 12 healthy volunteers. Each subject received 3 single doses of stiripentol (500, 1000, and 2000 mg) separated by a wash-out period of 1 week. Pharmacokinetics of stiripentol was analyzed for each dose by non-compartmental analysis. Median area under the curve (AUC), terminal elimination half-life (t1/2,z) and maximal concentration (Cmax) were calculated for between-dose comparison. Safety was evaluated based on both clinical and biological criteria. Oppositely to previous results, there was no concentration rebounds in the elimination phase, which could be the consequence of the food intake. A more than proportional increase in the AUC was observed, associated with a significant increase in the t1/2,z, for increasing doses (median AUC of 8.3, 31 and 88 mgh/L, and median t1/2,z of 2, 7.7 and 10h for the 500, 1000, and 2000 mg doses respectively), which confirmed the Michaelis-Menten pharmacokinetics of Stiripentol. However, dose-normalized Cmax did not significantly vary between doses. Median Michaelis-Menten parameters were 117 mg/h for Vmax and 1.9 mg/L for Km. No safety concern was observed during the study. The present study allowed a better characterization of the disposition phase of stiripentol and confirmed its non-linear pharmacokinetic behaviour. Further pharmacokinetic/pharmacodynamic studies would be useful to determine the optimal dose of stiripentol for the treatment of Dravet patients in adulthood.
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, PRES Sorbonne Paris Cité, France; CEA Gif-sur-Yvette, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Peigné
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, PRES Sorbonne Paris Cité, France; CEA Gif-sur-Yvette, France; Service de Pharmacologie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rey
authors.affiliation: Laboratoires BIOCODEX, 7 avenue Gallieni, 94250 Gentilly, France.
authors.forename: Marie-Emmanuelle
authors.initials: ME
authors.lastname: Le Guern
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, PRES Sorbonne Paris Cité, France; CEA Gif-sur-Yvette, France; Service de Neuropédiatrie, Groupe Hospitalier Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, PRES Sorbonne Paris Cité, France; CEA Gif-sur-Yvette, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chiron
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, PRES Sorbonne Paris Cité, France; CEA Gif-sur-Yvette, France; Service de Pharmacologie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pons
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, PRES Sorbonne Paris Cité, France; CEA Gif-sur-Yvette, France; Service de Pharmacologie, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: vincent.jullien@egp.aphp.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001774:Blood Chemical Analysis; D018592:Cross-Over Studies; D004148:Dioxolanes / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D016014:Linear Models; D008297:Male; D017711:Nonlinear Dynamics; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; C021092:stiripentol
keywords: Adults; Pharmacokinetics; Stiripentol