Change in clobazam pharmacokinetics after introduction of cenobamate

Cenobamate is a new antiseizure medication with an unusually high seizure-free rate, resulting in frequent use in patients with drug-resistant epilepsy. Many of these patients are taking clobazam (CLB) at baseline. Cenobamate has important interactions with CLB, requiring CLB dose adjustment in conjunction with cenobamate titration. There is limited guidance on the optimal CLB dose adjustment after cenobamate introduction and titration. We measured levels of CLB and its active metabolite N-desmethylclobazam (N-CLB) before and after cenobamate titration in 10 subjects with drug-resistant focal epilepsy. The mean CLB dose at baseline was 34.5 mg/day (range = 15-60 mg/day). We empirically started reducing the dose of CLB when starting 25 mg of cenobamate, then we cut the CLB dose down to 10 or 5 mg when reaching a cenobamate dose of 50 mg daily. The mean final dose of CLB was 9 mg (74% reduction). The average combined CLB + N-CLB level after cenobamate titration was 2191 μg/mL, not significantly different from baseline (2358 μg/mL). Although there may be individual variability, a 70%-74% CLB dose reduction may be appropriate to achieve an equivalent combined CLB + N-CLB level.