Pharmacokinetics and safety of cenobamate,a novel antiseizure medication,in healthy Japanese,and an ethnic comparison with healthy non‐Japanese

Cenobamate (XCOPRI and ONTOZRY) is a novel antiseizure medication for the treatment of focal‐onset seizures. Nonetheless, there is limited information on the pharmacokinetics (PKs), safety, and efficacy of cenobamate in Asian people, including Japanese people. This study aimed to evaluate the PKs and safety of cenobamate after a single oral dose in healthy Japanese subjects and to compare the PKs with that reported in non‐Japanese subjects. A randomized, double‐blind, placebo‐controlled, single ascending dose study was conducted at four dose levels of 50, 100, 200, and 400 mg. Subjects were randomly assigned to cenobamate or placebo in a 6:2 ratio. Cenobamate was rapidly absorbed, reaching its maximum plasma concentration (C_max) in 0.75 to 2.25 h, and was eliminated with a mean half‐life of 37.0 to 57.7 h. The C_max increased dose proportionally, whereas area under the concentration‐time curve increased more than dose proportionally, which was consistent with the findings in non‐Japanese subjects. The systemic exposure of cenobamate was comparable between Japanese and non‐Japanese subjects at all dose levels evaluated. All adverse events were mild in severity, and their incidence did not show dose‐dependent trends. Furthermore, there were no clinically significant issues in safety parameters, including sedation tests, neurologic examinations, and Columbia Suicide Severity Rating Scale interviews. In conclusion, the systemic exposure of cenobamate after a single dose in Japanese subjects increased by dose, which was similar to the pattern in non‐Japanese subjects. In addition, a single dose of cenobamate was well‐tolerated in the dose range of 50 to 400 mg in healthy Japanese subjects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Cenobamate is a novel antiseizure medication newly approved for the treatment of focal‐onset seizures in the United States and Europe. To date, properties of cenobamate including pharmacokinetics (PKs) have not been extensively studied in Asian people including Japanese people.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the PKs and safety of a single oral dose of cenobamate in healthy Japanese subjects and compared the PKs with that in non‐Japanese subjects previously reported.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Cenobamate showed similar PK profiles in Japanese and non‐Japanese subjects, which suggests its negligible ethnic sensitivity. In addition, a single dose of cenobamate was well‐tolerated in healthy Japanese subjects. Our results indicate that the currently approved dosing regimen of cenobamate may also be applicable to Japanese patients with reasonable exposure and tolerability profiles.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study bridged the clinical pharmacology gap between ethnicities by providing new findings on the ethnic sensitivity as well as the PKs and safety of cenobamate in Asian people including Japanese people.