Document Detail


Clobazam therapeutic drug monitoring: a comprehensive review of the literature with proposals to improve future studies.
MedLine Citation:
PMID:  23318278     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Clobazam was recently approved for Lennox-Gastaut syndrome in the United States. There is no published review article focused on clobazam therapeutic drug monitoring (TDM) in English.
METHODS: More than 200 clobazam articles identified by a PubMed search were carefully reviewed for information on clobazam pharmacokinetics. Clobazam is mainly metabolized by a cytochrome P450 (CYP) isoenzyme, CYP3A4, to its active metabolite, N-desmethylclobazam. Then, N-desmethylclobazam is mainly metabolized by CYP2C19 unless the individual has no CYP2C19 activity [poor metabolizer (PM)].
RESULTS: Using a mechanistic approach to reinterpret the published findings of steady-state TDM and single-dosing pharmacokinetic studies, 4 different serum clobazam concentration ratios were studied. The available limited steady-state TDM data suggest that the serum N-desmethylclobazam/clobazam ratio can be useful for clinicians, including identifying CYP2C19 PMs (ratio >25 in the absence of inhibitors). There are 3 possible concentration/dose (C/D) ratios. The clobazam C/D ratio has the potential to measure the contribution of CYP3A4 activity to the clearance of clobazam from the body. The N-desmethylclobazam C/D ratio does not seem to be a good measure of clobazam clearance and should be substituted with the total (clobazam + N-desmethylclobazam) C/D ratio.
CONCLUSIONS: Future clobazam TDM studies need to use trough concentrations after steady state has been reached (>3 weeks in normal individuals and several months in CYP2C19 PMs). These future studies need to explore the potential of clobazam and total C/D ratios. Better studies on the relative potency of N-desmethylclobazam compared with the parent compound are needed to provide weighted total serum concentrations that correct for the possible lower N-desmethylclobazam pharmacodynamic activity. Standardization and more studies of C/D ratios from clobazam and other drugs can be helpful to move TDM forward.
Authors:
Jose de Leon; Edoardo Spina; Francisco J Diaz
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Therapeutic drug monitoring     Volume:  35     ISSN:  1536-3694     ISO Abbreviation:  Ther Drug Monit     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-15     Completed Date:  2013-09-26     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  7909660     Medline TA:  Ther Drug Monit     Country:  United States    
Other Details:
Languages:  eng     Pagination:  30-47     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticonvulsants / analysis*,  pharmacokinetics,  therapeutic use
Aryl Hydrocarbon Hydroxylases / metabolism
Benzodiazepines / analysis*,  pharmacokinetics*,  therapeutic use
Cytochrome P-450 CYP3A / metabolism
Drug Monitoring / methods*
Humans
Intellectual Disability / drug therapy,  enzymology,  metabolism
Spasms, Infantile / drug therapy,  enzymology,  metabolism
Grant Support
ID/Acronym/Agency:
UL1 TR000001/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Anticonvulsants; 12794-10-4/Benzodiazepines; 2MRO291B4U/clobazam; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C19 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A; MZ4L647O2H/N-desmethylclobazam
Comments/Corrections

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