Abstracts

Rationale: Cenobamate (CNB) is a recently FDA-approved anti-seizure medication (ASM) for the treatment of adults with focal epilepsy. CNB is an inducer of CYP3A substrates and an inhibitor of CYP2C19 substrates, leading to multiple interactions with concomitant ASM. A recent phase 3 trial showed that CNB was relatively safe and well tolerated, however there is limited data available on interactions between CNB and other ASM. We report our clinical experience using CNB and the interactions we have observed with concomitant use of clobazam (CLB). CLB is metabolized by CYP3A4 to its active N-desmethylclobazam (N-CLB) metabolite, which is later metabolized by CYP2C19.

Methods: We retrospectively identified 18 adult patients treated with CNB in our epilepsy center and reviewed their medical records. Pertinent data points (seizure control, medications, side effects) were extracted for further analysis.

Results: Six patients (age range 25-58) used concomitant CNB and CLB. All patients had focal drug resistant epilepsy (DRE), were taking upwards of 4 ASMs in variable combinations, and 5 patients had prior surgical intervention (1 resection, 2 VNS and 4 RNS implantations). Most frequently used concurrent ASMs included lamotrigine and topiramate, followed by lorazepam, clonazepam, zonisamide, levetiracetam and eslicarbazepine. CNB 12.5 mg/day was initiated and increased in 2-week intervals based on tolerability and seizure reduction. CNB dosages ranged from 25 mg to 250 mg daily and baseline CLB dosages ranged from 30 mg to 80 mg daily. CLB was reduced by 50% or more in 4 patients following initiation of CNB. Side effects were reported at doses of CNB 100 mg daily or greater, except one patient who reported intolerable side effects at 25 mg. Two patients (P1-2) discontinued CNB at dosages of 25 mg and 100 mg daily respectively. Four other patients (P3-6) continued using CNB dosages of 150-250 mg daily. Two patients (P5-6) developed clinical signs of toxicity including lethargy, imbalance, falls, and slurred speech that later resolved with a 50% CLB reduction. Patients on a combination of CNB-CLB (N=4) reported seizure improvement, with 3 experiencing significant seizure reduction with intervals of seizure freedom not previously attained with other ASM combinations. One patient (P5) had seizures reoccur after CLB discontinuation during an interval of seizure freedom, with significant improvement in seizures after reinstitution of CLB 10 mg daily (previous dose 50 mg daily).

Conclusions: There is a clinically significant pharmacokinetic interaction between CNB and CLB, likely due to accretion of N-CLB secondary to the CNB inhibition of CYP2C19 substrates. It is rarely practical to obtain CLB/N-CLB levels, thus a preemptive decrease in CLB after CNB initiation should be strongly considered for CNB dosages of 100 mg and above. While seizure reduction was present in our small cohort, a CLB reduction of 50% or more was required to resolve toxicity. Our experience adds to the limited, though encouraging, available data of CNB-CLB interactions and possible improved efficacy on this combination.

Funding: Please list any funding that was received in support of this abstract.: None.