期刊
CLINICAL PHARMACOKINETICS
卷 54, 期 5, 页码 527-536出版社
ADIS INT LTD
DOI: 10.1007/s40262-014-0223-5
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资金
- Biocodex
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 (R) software). Four blood samples were drawn per patient. Area under the plasma concentrationtime 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 Ctrough 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.
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