Table 7. Preclinical Toxicology Summary of Compound 25.
| 25 (BIIB129) | |
|---|---|
| In Vitro Safety Profile | |
| Cyp DDI IC50 [μM] | 2C9 = 5.2 |
| Cyp TDI (fold change over control) | 3A4 1-fold |
| 2C9 0.5-fold | |
| hERG IC50 [μM] | >30/>30 |
| radio ligand/patch clamp | |
| NaV 1.5/CaV 1.2 | >30/>30 |
| IC50 [μM] | |
| cytotox. Glu/Gal | >30/>30 |
| IC50 [μM] | |
| Ames | negative |
| micronucleus | negative |
| chromosomal aberration | negative |
| 3T3 NRU phototoxicity | negative |
| hepatotoxicity (HUREL human primary hepatocyte microliver) | minimal toxicity (ATP) |
| In Vivo Toxicology Studies | |
| rat micronucleus | negative |
| cynomolgus monkey cardiovascular | no adverse findings |
| 10, 30, 100 mg/kg | |
| rat 28-day | NOAEL = 200 mg/kg/day (365× male, 689× female safety marginsa) |
| 30, 100, 300 mg/kg BID | |
| cynomolgus monkey 28-day | NOAEL = 60 mg/kg/day (140× male, 136× female safety marginsa) |
| 10, 30, 100 mg/kg BID | |
a
Free peripheral AUC margin based on the projected human efficacious exposure.