Distribution, Metabolism, and Excretion of Cenobamate in Adult, Fetal, Neonatal, and Lactating Rats.

Abstract

Background and objective: Cenobamate is an antiseizure medication (ASM) approved for treatment of focal epilepsy in adults. The objective of this study was to characterize the distribution, metabolism, and excretion of cenobamate in adult and pre- and postnatal rats, including pregnant and lactating females and nursing pups.

Methods: Distribution, metabolic, and excretion profiles were determined for ¹⁴C-labeled and unlabeled cenobamate using liquid scintillation counting, radiochromatography, LCMS, and LCMS/MS after oral or intravenous (IV) administration.

Results: Distribution of ¹⁴C-cenobamate-related material in adult male rats was widespread throughout the body, with nearly 1:1 tissue-to-plasma ratios observed for most tissues, including brain. Cenobamate administered to pregnant females was also transferred across the placental barrier into amniotic fluid and fetal plasma. Following administration to lactating F₀ females, cenobamate was detected in breast milk and in plasma of nursing pups. ¹⁴C-cenobamate administered to adult male rats as a single oral dose was extensively metabolized with nine metabolites identified in urine and feces, including a principal dihydrodiol metabolite. Cenobamate was the principal drug-related material in rat plasma. Following a single dose of ¹⁴C-cenobamate to male and female rats, radioactivity was excreted equally into urine and feces, with mass balance achieved by 48 h postdose.

Conclusions: Distribution of cenobamate was widespread into many rat tissues, including brain, amniotic fluid, fetal plasma, breast milk, and breastfeeding rat pups. These distribution findings, along with the results of the metabolism and excretion studies, may help inform treatment decisions for patients with epilepsy being treated with cenobamate, including pregnant or nursing mothers.