Abstracts

Rationale:
Cenobamate (CNB), approved in the US to treat focal seizures in adults, is a weak/moderate dose related inducer of CYP3A and a moderate inhibitor of CYP2C19. Clobazam (CLB), approved for treatment of seizures associated with Lennox-Gastaut syndrome, is also used to treat focal seizures. CLB is mainly metabolized by CYP3A4 to its active N-desmethylclobazam (N-CLB) metabolite which is then metabolized by CYP2C19. We report our experience using CNB and CLB in a large Phase 3 open-label safety study of CNB for patients with uncontrolled focal seizures taking up to 3 anti-seizure medications (ASM).
Method:
CNB was started at 12.5mg/d in 6 patients taking CLB and other ASM and titrated every 2 wks to 25mg, 50mg, 100mg and 150mg to a target of 200mg/d. Titration by 50mg every 2 wks to a maximum of 400mg/d was allowed.  Doses of CNB, CLB and other ASMs could be adjusted and ASMs could be added.  Random serum concentrations of CLB (ref 30-300ng/ml) and N-CLB (ref 300-3000ng/ml) were obtained once in 5/6 patients during treatment.  CLB 5mg/d was added to the ASM regimen of 5 additional patients with persistent seizures after titration of CNB to maximal dose. Responder rates were calculated from daily seizure diaries.
Results:
Baseline CLB doses were 20 to 50 mg (mean 37.5). Sedation began in the 6 CLB patients at CNB doses of 25-100 mg (100mg in 3, 50mg in 2, 25mg in 1).  CLB concentrations in 4 patients when CNB doses were 100—200mg/d ranged from 77-332ng/ml and N-CLB levels ranged from 4930 to 13433 ng/ml. In these 4 patients, the N-CLB/ CLB ratio was >25 in 2 (1 on 200mg/d and 1 on 150mg/d) and >10 in 2 on 100mg/d.   CLB was stopped in all 6 patients.  In the month before CLB was stopped, 3 patients had >75% seizure reduction and 2 others were free of disabling seizures.  Two months after stopping CLB, only one patient still had >75% improvement in the preceding month.  CLB was restarted at 5 mg/d in 5 of the 6 patients.  In the month after restarting CLB 3 patients responded (2 >50% reduction and 1 seizure-free).  One of these patients had a CLB level of 10ng/ml and a N-CLB level of 1069 ng/ml while taking CNB 400mg/d. At last follow-up 4/6 patients were continuing CLB; 2 seizure-free (15 months and 3 months) and 2  >50% responders.   Among the 5 other patients that added 5mg/d CLB, 2 had >50% reduction, 1 became seizure-free (8 months), and 2 stopped CLB due to adverse effects.
Conclusion:
There is a clinically relevant pharmacokinetic interaction between CNB and CLB, with accumulation of N-CLB. Because of the potential for an increase in adverse reactions from CLB when starting CNB, reduction of CLB dose should be strongly considered starting at CNB doses of 25-100 mg/d.  The improvement in seizure control after reintroduction of CLB favors CLB dose reduction rather than elimination as the best approach when starting cenobamate.  In patients still having seizures on cenobamate addition of CLB starting at low doses should be considered, because of evidence of improved efficacy on this combination.
Funding:
:Supported by: SK Life Science, Inc.