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

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) 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/ 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/ F and 0.0706 h (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 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. [ABSTRACT FROM AUTHOR]