Rationale:
Concomitant antiseizure medications may affect the metabolism of clobazam (CLB) and its active metabolite N-desmethylclobazam (N-CLB). The conversion of CLB to N-CLB is mediated by CYP3A4, while the conversion of N-CLB to inactive metabolites is mediated by CYP2C19. We reviewed the effect of different concomitant antiseizure medications (ASMs) on the ratio of N-CLB to CLB concentration, including those ASMs known to influence CYP3A4 or CYP2C19 activity.
Methods: CLB and N-CLB concentrations were measured during clinical practice in patients treated with CLB for drug-resistant seizures. We analyzed serum concentrations and their ratios in relation to concomitant ASMs. We combined instances of concomitant ASMs not known to interact with either CYP3A4 or CYP2C19 and used their data for reference.
We included analyses of interacting ASMs if they had at least five measurements. We used the Mann–Whitney U test for comparisons.
Results: Serum concentrations were obtained in 224 instances, in 119 patients. A total of 100 measurements were obtained in 65 patients not taking any CYP3A4/ CYP2C19 inducers or inhibitors. The mean N-CLB/CLB ratio was 5 +/- 4.3 and the median was 4. The range was 1-15 with one outlier of 36. The interacting ASMs with at least 5 measurements included cenobamate, oxcarbazepine, eslicarbazepine acetate, felbamate, and topiramate. For 37 measurements with adjunctive cenobamate (22 patients), the ratio mean was 35 and median 28 (range 6-130). The difference from the reference group was highly significant (p< 0.00001). The ratio was also significantly higher than reference for the groups taking oxcarbazepine (ratio mean, median of 15, 13; 13 measurements in eleven subjects), eslicarbazepine acetate (ratio mean, median of 7, 7; 6 measurements in three subjects), and felbamate (ratio mean, median of 25, 23; 9 measurements in 5 subjects). The ratio was not different from reference for patients taking topiramate (ratio mean, median of 8, 5; 17 measurements in eleven subjects).