Authors :
Presenting Author: Barbara Kwiecinska, MD – Vanderbilt University Medical Center
Richa Budhiraja, MBBS – Vanderbilt University Medical Center
Melissa Osborn, RN – Vanderbilt University Medical Center
Kevin Haas, MD, PhD – Vanderbilt University Medical Center
Bassel Abou-Khalil, MD – Vanderbilt University Medical Center
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 2 concomitant antiseizure medications (ASMs) known to influence CYP3A4 or CYP2C19 activity on the ratio of N-CLB to CLB concentration and on the clearance of CLB and N-CLB.
Methods:
CLB and N-CLB concentrations were measured during clinical practice in patients treated with CLB for drug-resistant seizures. We performed a chart review to identify patients who had CLB and N-CLB levels. We identified patients taking cenobamate or oxcarbazepine/eslicarbazepine acetate. Controls were patients not taking interacting ASMs. We excluded patients taking multiple interacting ASMs. We calculated the N-CLB/CLB ratio, as well as CLB and N-CLB clearance. We used the Mann–Whitney U test for comparisons.
Results:
123 CLB and N-CLB serum concentrations were obtained in patients not taking any CYP3A4/ CYP2C19 inducers or inhibitors, 32 in patients taking oxcarbazepine or eslicarbazepine acetate, and 46 in patients taking cenobamate. The mean control N-CLB/CLB ratio was greater for both OXC/ESL (14) and CNB (32) as compared to controls (5). The mean CLB clearance was greater for both OXC/ESL (110 L/day) and CNB (146 L/day) as compared to controls (78 L/day), while the N-CLB clearance was decreased for both OXC/ESL (10 L/day) and CNB (5 L/day), as compared to controls (27 L/day). The CLB clearance was dose dependent for both OXC/ESL (comparing OXC dose of 2400 compared with OXC/ESL dose of 1200) and CNB (comparing CNB dose of 400 and CNB dose of 100), while N-CLB clearance was not dose dependent.
Conclusions:
Cenobamate had the greatest impact on N-CLB/CLB ratio and the CLB and N-CLB clearance. OXC/ESL had a lower impact. The clearance of CLB was dose dependent while the clearance of N-CLB was not, suggesting that the inhibition of CYP2C19 was already maximal at OXC dose of 1200 and CNB dose of 100, while the induction of CYP3A4 increased at the higher doses.
Funding: none