Clobazam therapeutic drug monitoring: a comprehensive review of the literature with proposals to improve future studies.

Article Details

Citation

de Leon J, Spina E, Diaz FJ

Clobazam therapeutic drug monitoring: a comprehensive review of the literature with proposals to improve future studies.

Ther Drug Monit. 2013 Feb;35(1):30-47. doi: 10.1097/FTD.0b013e31827ada88.

PubMed ID
23318278 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
ClobazamCytochrome P450 2C19ProteinHumans
No
Substrate
Details
ClobazamCytochrome P450 3A4ProteinHumans
No
Substrate
Inducer
Details