Change in Clobazam Pharmacokinetics After Introduction of Cenobamate
Abstract number :
3.427
Submission category :
7. Anti-seizure Medications / 7E. Other
Year :
2024
Submission ID :
161
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Melissa Osborn, BSN – Vanderbilt University Medical Center
Kevin Haas, MD, PhD – Vanderbilt University Medical Center
Bassel Abou-Khalil, MD – Vanderbilt University Medical Center
Rationale: Clobazam (CLB) is a broad spectrum antiseizure medication used frequently in subjects with drug-resistant epilepsy. Clobazam is converted to an active metabolite, N-desmethylclobazam (N-CLB) via CYP3A4, which is then metabolized to inactive compounds via CYP2C19. Clobazam metabolism is affected by inducers and inhibitors of CYP3A4 and CYP2C19. In particular, cenobamate (CNB) is an inducer of CYP3A4 and inhibitor of CYP2C19. This is expected to accelerate the conversion of CLB to N-CLB and cause accumulation of N-CLB. An adjustment of CLB dosage is required during CNB titration. However, the extent of the required adjustment is not well defined.
Methods: We identified patients who were taking CLB before starting cenobamate titration for drug-resistant seizures, and who had CLB and N-CLB concentrations measured before and after CNB titration. In view of the known CLB-CNB interaction, we empirically start reducing the dose of CLB when starting 25 mg of CNB, then we cut the CLB dose down to 10 or 5 mg when reaching a CNB dose of 50 mg daily. We compared pre- and post- CNB levels of CLB, N-CLB, and CLB+N-CLB; CLB level/ CLB dose; N-CLB level/ CLB dose; and N-CLB/CLB ratios. We used the Wilcoxon test to compare pre- and post-CNB values.
Results: Ten subjects received levels of CLB and N-CLB before then after titration of CNB to at least 100 mg daily (Table). The baseline total daily CLB dose ranged from 15 mg to 60 mg (median 30 mg). By the time of the next levels after titration of CNB the total daily dose of CLB ranged from 5 mg to 10 mg (median 10 mg), reflecting a 74% mean dose reduction. The CLB level dropped by 81% (P< 0.01), while the NCLB level increased by 12% (NS). The combined CLB+N-CLB level dropped by 7% (+/- 45%; NS). The CLB level/ CLB dose ratio decreased by 31% (p< 0.05), while the N-CLB level / CLB dose increased by 347% (p< 0.01). The N-CLB/CLB level ratio increased 709% from a mean of 3.8 to a mean of 30.4 (p< 0.01). Nine of the 10 patients have continued the combination of CLB+CNB for longer than one year.
Anti-seizure Medications