Table 5.
Anticonvulsant activity of cenobamate in mice (multiple studies).
| Type of Seizure Model | Seizure Model (STUDY) | Drug, Route & Dose | N per dose group | ED50 mg/kg (95% CI) | TD50 mg/kg (95% CI) | Protective Indexa | Additional Findings | |
|---|---|---|---|---|---|---|---|---|
| Chemically induced | SC PTZ 85 mg/kg (NINDS) | CBM IP 12, 22, 40, 95 mg/kg | 8 | 28.5 (19.6–42.3) | 58.0 (39.5–74.1) | 2.0 | Inhibition | |
| SC PTZ 95.2 mg/kg (F) | CBM IP 3, 5, 8, 12 mg/kg | 8 | 3.8 (2.3–6.2) | NT | NA | DD inhibition | ||
| ESM IP 70, 80, 90, 100 mg/kg | 8 | 96.2 (77.3–96.1) | NT | NA | DD inhibition | |||
| CBM PO 5, 7, 10 mg/kg | 8 | 7.1 (5.3–9.4) | NT | NA | DD inhibition | |||
| ESM PO 200, 250, 300 mg/kg | 8 | 210.6 (181–245) | NT | NA | DD inhibition | |||
| SC PTZ 85 mg/kg (G) | CBM IP 10, 14, 17, 30 mg/kg | 8–10 | 14.8 (12.6–17.5) | NT | NA | DD inhibition | ||
| VPA IP 150 mg/kg | 8 | NA | NT | NA | 2/8 mice protected | |||
| SC bicuculline 2.7 mg/kg (NINDS) | CBM IP 30, 70 mg/kg | 8 | >70 (−) | 58.0 (39.5–74.1) | <0.8 | No inhibition | ||
| SC bicuculline 3.4 mg/kg (J) | CBM IP 10, 20, 30 mg/kg | 8 | 17.3 (10.9–27.8) | NT | NA | DD inhibition | ||
| VPM IP 400, 450, 500 mg/kg | 8 | 468.7 (442–497) | ||||||
| SC bicuculline 3.5 mg/kg (K) | CBM IP 10, 20, 30, 40, 50 mg/kg | 10 | 35.4 (−) | NT | NA | DD inhibition from 10 to 40 mg/kg | ||
| DZP IP 5 mg/kg | 7 | NA | NT | NA | 7/7 mice protected | |||
| SC picrotoxin 2.5 mg/kg (NINDS) | CBM IP 25, 30, 35, 70 mg/kg | 8 | 34.5 (25.9–48.8) | 58.0 (39.5–74.1) | 1.7 | Inhibition | ||
| SC picrotoxin 4.5 mg/kg (L) | CBM IP 10, 20, 30 mg/kg | 8 | 23.2 (14.9–36.2) | NT | NA | DD inhibition | ||
| VPA IP 200, 300, 350, 400 mg/kg | 8 | 341 (307–380) | ||||||
| Electrically induced | 6 Hz (NINDS) | 22 mA | CBM IP 5.4, 10, 15, 20 mg/kg | 8 | 11.0 (6.9–15.4) | 58.0 (39.5–74.1) | 5.3 | – |
| 32 mA | CBM IP 10, 17, 21, 25 mg/kg | 8–16 | 17.9 (14.9–21.1) | 3.2 | – | |||
| 44 mA | CBM IP 5.4, 10, 20, 25 mg/kg | 8 | 16.5 (11.6–22.6) | 3.5 | – | |||
| MES (NINDS) | CBM IP 6, 8, 15, 23 mg/kg | 8 | 9.8 (7.8–12.9) | 58.0 (39.5–74.1) | 5.9 | Inhibition | ||
| MES (A) | CBM IP 3, 8, 12, 15 mg/kg | 8 | 4.2 (2.7–6.7) | NT | NA | DD inhibition | ||
| PHT IP 1,2, 5 mg/kg | 8 | 2.8 (1.5–5.3) | NT | NA | DD inhibition | |||
| CBM PO 2, 4, 7, 10 mg/kg | 8 | 3.3 (2.2–5.0) | NT | NA | DD inhibition | |||
| PHT PO 1,2, 5 mg/kg | 8 | 6.8 (4.7–9.6) | NT | NA | DD inhibition | |||
| MES (B) | IP 3, 5, 7.5, 10 mg/kg | 10 | 7.0 (5.6–8.6) | NT | NA | DD inhibition | ||
| VPA IP 275 mg/kg | 10 | NA | NT | NA | 6/10 mice protected | |||
CBM, cenobamate; CI, confidence interval; DD, dose-dependent; DZP, diazepam; ED50, median effective dose; ESM, ethosuximide; IP, intraperitoneal; MES, maximal electroshock seizures; NA, not applicable/available; NINDS, National Institute of Neurological Disorders and Stroke; NT, not tested; PHT, phenytoin; PO, oral; PTZ, pentylenetetrazol; SC, subcutaneous; TD50, median neurotoxic dose; VPA, valproic acid/valproate.
aProtective index calculation TD50/ED50. TD50 based on rotarod test.