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 trough) 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 CLB/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 CLB/F and 0.0706 h(-1) (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 trough 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.
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 trough) 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 CLB/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 CLB/F and 0.0706 h(-1) (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 trough 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 epilepticchildren. 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.
Authors: Marion Bouillon-Pichault; Vincent Jullien; Caroline Bazzoli; Gérard Pons; Michel Tod Journal: J Pharmacokinet Pharmacodyn Date: 2010-11-04 Impact factor: 2.745
Authors: W Rupp; M Badian; O Christ; P Hajdú; R D Kulkarni; K Taeuber; M Uihlein; R Bender; O Vanderbeke Journal: Br J Clin Pharmacol Date: 1979 Impact factor: 4.335
Authors: A Tran; E Rey; G Pons; M Rousseau; P d'Athis; G Olive; G G Mather; F E Bishop; C J Wurden; R Labroo; W F Trager; K L Kunze; K E Thummel; J C Vincent; J M Gillardin; F Lepage; R H Levy Journal: Clin Pharmacol Ther Date: 1997-11 Impact factor: 6.875