title: Clobazam therapeutic drug monitoring:  a comprehensive review of the literature with proposals to improve future studies.
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.
authors: University of Kentucky Mental Health Research Center at Eastern State Hospital, Lexington, Kentucky 40508, USA. jdeleon@uky.edu
authors: Jose
authors: J
authors: de Leon
authors: Edoardo
authors: E
authors: Spina
authors: Francisco J
authors: FJ
authors: Diaz
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000032:analysis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001569:Benzodiazepines / Q000032:analysis* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D008607:Intellectual Disability / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D065768:Lennox Gastaut Syndrome; D013036:Spasms, Infantile / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C024581:N-desmethylclobazam