Effect of cenobamate on the single‐dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects

This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no‐effect interval (0.80–1.25). When co‐administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC_0–last) GMR (90% CIs) for midazolam was 0.734 (0.647–0.832). When co‐administered with cenobamate 200 mg/day, AUC_0–last GMRs (90% CI) for midazolam, bupropion, S‐warfarin, and omeprazole were 0.277 (0.238–0.323), 0.615 (0.522–0.724), 1.14 (1.10–1.18), and 2.07 (1.44–2.98), respectively. Co‐administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co‐administration of cenobamate led to omeprazole values which were outside and above the no‐effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co‐administration of cenobamate with these probes drugs was well‐tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose‐dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐drug interactions are a challenging aspect of managing epilepsy because many antiseizure medications (ASMs) induce or inhibit CYP450 enzymes, which are commonly involved in drug metabolism of many ASMs. Previous studies suggest that cenobamate, a US Food and Drug Administration (FDA)‐approved ASM for the treatment of adults with focal seizures, may affect the activity of certain CYP450 enzymes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study was designed to determine the effects of cenobamate on the pharmacokinetics of drugs known to affect the activity of these CYP450 enzymes, known as probe drugs. These probe drugs include bupropion, (CYP2B6), midazolam (CYP3A4/5), warfarin (CYP2C9), and omeprazole (CYP2C19).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of this study indicate that cenobamate induces CYP2B6 activity, exhibits a dose‐dependent induction of CYP3A4/5 activity, inhibits CYP2C19 activity, and has a negligible effect on CYP2C9 activity.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These findings suggest that dose adjustments may be required when agents metabolized through these CYP450 pathways are used in conjunction with cenobamate.