Rationale:
Cenobamate is an antiseizure medication (ASM) approved in the United States (XCOPRI®) and Europe (ONTOZRY®) for the treatment of focal seizures in adult patients. In some patients, oral administration is challenging, and crushing tablets offers additional options for administration, including dosing by nasogastric tube. This study examined pharmacokinetics (PK) and safety of crushed cenobamate tablets in suspension delivered orally and via nasogastric tube.
Methods:
Upon informed consent, 24 healthy subjects (ages 18-50 years) were enrolled into this open-label, randomized, single-center, 3-period, 6-sequence, balanced crossover study. Subjects received one dose each of cenobamate 200 mg as an intact tablet administered with 240 mL of water (treatment A, reference), a crushed tablet suspended in 240 mL of water and taken orally (treatment B, test 1), and a crushed tablet suspended in 240 mL of water and administered via nasogastric tube (treatment C, test 2). All doses were administered in a fasting state, with a 13-day washout between doses. Blood samples for PK assessments were collected from pre-dose to 264 hours following each treatment on Days 1, 14, and 27. Natural log-transformed cenobamate PK parameters (C
max, AUC
last, and AUC
0-inf) were used to estimate relative bioavailability and construct 90% confidence intervals (CIs) using a mixed-effects model approach, with treatment, sequence, and period as fixed effects and subject within sequence as random effect. An absence of effect was concluded if the 90% CIs fell within the 80%-125% predefined boundaries.
Results:
Test-to-reference ratios for treatment B versus reference (90% CIs) were: C
max, 95.6% (89.6%-102%); AUC
last, 90.9% (87.2%-94.7%); AUC
0-inf, 92.8% (89.6%-96.0%). Test-to-reference ratios for treatment C versus reference (90% CIs) were: C
max, 101.7% (95.4%-108.4%); AUC
last, 93.3% (89.6%-97.2%); AUC
0-inf, 94.1% (91.0%-97.3%) (
Figure 1).
Conclusions:
All 90% CIs of test-to-reference ratios for C
max, AUC
last, and AUC
0-inf were within 80%-125%, which demonstrated bioequivalence between all 3 cenobamate administration routes. These results support the administration of cenobamate as a crushed tablet orally or a crushed tablet via nasogastric tube, providing additional flexibility for dosing.
Funding: Funded by SK Life Science, Inc.