Table 3.
PK parameters of EC3039 and EC1728 administered to a satellite group of dogs for 5 days by oral gavage.
| Gender | Compound detected | Cmax (ng/mL) |
AUClast (h∗ng/mL) |
T1/2 (h) | |||
|---|---|---|---|---|---|---|---|
| Day 1 | Day 5 | Day 1 | Day 5 | Day 5 | |||
| EC3039 (1 mg/kg) | M | EC3039 | 400 | 2,300 | 2,490 | 72,100 | 33 |
| EC17281 | 5 | 101 | 26 | 6,370 | – | ||
| F | EC3039 | 568 | 17,300 | 3,940 | 361,000 | 40 | |
| EC1728 | 4 | 404 | 24 | 25,200 | – | ||
| EC3039 (5 mg/kg) | M | EC3039 | 16,900 | 32,100 | 46,500 | 463,00 | 27 |
| EC1728 | 54 | 772 | 295 | 50,200 | – | ||
| F | EC3039 | 18,000 | 30,900 | 67,200 | 589,000 | 25 | |
| EC1728 | 50 | 606 | 298 | 39,000 | – | ||
| EC1728 (1 mg/kg) | M | EC1728 | 330 | 1,900 | 1,690 | 32,000 | 27 |
| F | EC1728 | 308 | 4,660 | 1,350 | 155,000 | 33 | |
| EC1728 (5 mg/kg) | M | EC1728 | 1,100 | 1,930 | 3,760 | 96,300 | 25 |
| F | EC1728 | 1,160 | 4,990 | 4,940 | 53,200 | 23 | |
EC3039 had improved PK properties compared to EC1728. EC3039 had higher systemic exposure (Cmax and AUC) compared to EC1728, and exposure increased in a more than dose proportional manner for EC3039 and less than dose proportional manner for EC1728. Exposure for both compounds increased over the 5-days of dosing. 1EC1728 was detected in animals treated with EC3039, presumable from N-demethylation by CYP450; however, the T1/2 could not be calculated because it could not be fitted to a PK model.