Table 1.

Effect of cenobamate on the pharmacokinetics of concomitantly administered medications

Affected drug	Interaction caused by cenobamate	Probable mechanism	Comment	References
Antiseizure medications
Carbamazepine	23% decrease in carbamazepine AUC	Induction of CYP3A	Effect observed following exposure to multiple dosing with cenobamate (200 mg/day)	Prescribing information [77]; Vernillet et al. [99]
Clobazam	Prominent increase in plasma N-desmethylclobazam concentration	Inhibition of CYP2C19	In a retrospective study of 5 patients, the increase in plasma levels of N-desmethylclobazam, the active metabolite of clobazam, ranged from 145 to 1852% and was associated with fatigue, which improved after reducing the clobazam dose [95]. Another study reported similar findings and provided suggestive evidence of cenobamate and clobazam may also exhibit synergic therapeutic efficacy [96]	Elakkari et al. [95]; Osborn and Abou-Khalil [96]
Lamotrigine	21–51% decrease in plasma lamotrigine concentrations	Induction of lamotrigine glucuronidation	Estimates based on population pharmacokinetics analysis at a cenobamate dose of 100–400 mg/day	Prescribing information [77]; Vernillet et al. [99]
Phenobarbital	37% increase in phenobarbital AUC	Inhibition of CYP2C19 (?)	Effect observed following exposure to multiple dosing with cenobamate (200 mg/day)	Prescribing information [77]; Vernillet et al. [99]
Phenytoin	84% increase in phenytoin AUC	Inhibition of CYP2C19 (?)	Effect observed following exposure to multiple dosing with cenobamate (200 mg/day)	Prescribing information [77]; Vernillet et al. [99]
Other drugs
Bupropion	39% decrease in bupropion AUC	Induction of CYP2B6	Bupropion (150 mg) was given orally as a probe substrate to test the effect of cenobamate (200 mg/day) on CYP2B6 activity. The decrease in plasma concentrations of bupropion was associated with increased plasma concentrations of the active metabolite hydroxybupropion	Prescribing information [77]; Greene et al. [94]
Midazolam	72% decrease in midazolam AUC	Induction of CYP3A	Midazolam (2 mg) was given orally as a probe substrate to test the effect of cenobamate (200 mg/day) on CYP3A activity. At a dose of 100 mg/day, the mean decrease in midazolam AUC was 27%	Prescribing information [77]; Greene et al. [94]
Omeprazole	107% increase in omeprazole AUC	Inhibition of CYP2C19	Omeprazole (20 mg) was given orally as a probe substrate to test the effect of cenobamate (200 mg/day) on CYP3A activity	Prescribing information [77]; Greene et al. [94]

AUC area under the plasma drug concentration–time curve, CYP cytochrome P450