Table 8.
Anticonvulsant activity of cenobamate in rats (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 Indexb | Additional Findings |
|---|---|---|---|---|---|---|---|
| Chemically induced | SC PTZ 56.4 mg/kg or 68 mg/kg (NINDS)a | CBM IP 4, 8, 16, 24, 32 mg/kg | 8 | 13.6 (6.6–25.0) | 38.9 (32.2–43.9) | 2.9 | Inhibition |
| CBM PO 12.5, 25, 50, 100 mg/kg | 2–10 | >100 (−) | 50.7 (35.7–63.0) | NA | Maximum 40% protection at 25 mg/kg | ||
| SC PTZ 105.8 mg/kg (H) | CBM PO 5, 10, 20 mg/kg | 8 | 8.3 (5.5–12.3) | NT | NA | DD inhibition | |
| SC PTZ 70 mg/kg (I) | CBM, PO 10, 30, 60 mg/kg | 8 | 20.3 (−) | NT | NA | DD inhibition | |
| VPA IPO 200 mg/kg | 6 | NA | NT | NA | 3/6 rats protected | ||
| Electrically induced | Hippocampal kindling (NINDS) | CBM IP 10, 15, 22.5, 30 mg/kg | 7–8 | 16.4 (12.7–20.2) | 38.9 (32.2–43.9) | 2.4 | See Fig. 2 |
| MES (NINDS) | CBM IP 1.5, 3, 4.5, 6 mg/kg | 8 | 2.9 (1.9–3.8) | 38.9 (32.2–43.9) | 14 | Inhibition | |
| CBM PO 0.75, 1.5, 3, 4.5 mg/kg | 8 | 1.9 (0.9–3.3) | 50.7 (35.7–63.0) | 27 | |||
| MES (C) | CBM PO 0.3, 0.6, 1, 3 mg/kg | 8 | 0.4 (0.3–0.8) | NT | NA | DD inhibition | |
| CBZ PO 10 mg/kg | 8 | NA | NT | NA | 6/8 rats protected | ||
| MES (D) | CBM PO 0.1, 0.3, 1, 3 mg/kg (3 batches; 1401-1401-07-001; 1401-1401-05-501; DIT040503) | 6–8 | 0.3 (−) | 101.6 (27.9–220.1) | 339c | Dose-related inhibition similar across different batches | |
| 6–8 | 0.3 (−) | 104.1 (40.0–204.4) | 347c | ||||
| 6–8 | 0.7 (−) | 100.4 (−2.0-305.9) | 143c | ||||
| CBZ PO 10 mg/kg | 8 | NA | NT | NA | 6/8 rats protected |
CBM, cenobamate; CBZ, carbamazepine; DD, dose-dependent; ED50, median effective dose; IP, intraperitoneal; MES, maximal electroshock seizures; NA/-, not applicable/available; NINDS, National Institute of Neurological Disorders and Stroke; NT, not tested; PO, oral; PTZ, pentylenetetrazol; SC, subcutaneous; TD50, median neurotoxic dose; VPA, valproic acid/valproate.
a56.4 mg/kg for rats sourced from Simonsen Laboratories, Inc. and 68 mg/kg for rats sourced from Charles River Laboratories.
bProtective index calculation TD50/ED50. TD50 based on minimal motor impairment or crotarod impairment.