Clobazam Therapeutic Drug Monitoring

Abstract

Background Clobazam was recently approved for Lennox-Gastaut syndrome in the US. There is no published review article focused on clobazam therapeutic drug monitoring (TDM) in English. Methods More than two hundred 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, four 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 three 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 appear 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 to 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.

Three Patients Needing High Doses of Valproic Acid to Get Therapeutic Concentrations

“…The senior author has used the C/D ratio to interpret TDM of clobazam [ 27 ], clozapine, and risperidone [ 28 ]. These 3 drugs, like the majority of drugs used in neuropsychopharmacology, follow linear kinetics.…”

PharmGKB summary

“…The different half-lives of clobazam and norclobazam are reflected in the time needed for both drugs to reach steady state concentrations. In multi-dose studies, clobazam reaches a steady-state concentration within one week of beginning treatment, while a steady-state concentration of norclobazam can take up to 3 weeks to be established [18, 20]. Steady-state concentrations of norclobazam have been found to be higher in females than in males [19].…”

“…Similarly, induction of CYP2C19 increases norclobazam elimination from the body [36]. There have been indications that clobazam is itself a CYP3A4 inducer and could therefore self-induce its own metabolism [20, 39], but these have yet to be fully confirmed. Clobazam is known to inhibit CYP2D6, affecting the pharmacokinetics of drugs such as dextromethorphan, which undergoes an 95% increase in its AUC in the presence of clobazam [15].…”

Buprenorphine–cannabis interaction in patients undergoing opioid maintenance therapy

“…Analysis of buprenorphine and norbuprenorphine in blood may support the clinician regarding the need for changes in drug dosage or administration patterns and enables detection of non-compliance. In particular, the drug concentration-to-dose ratio in conjunction with the metabolite-to-parent drug ratio presents a valid parameter for assessing compliance [15,16].…”