Table 6.
4-week IV repeat-dose toxicity studies in cynomolgus monkeys; mean TK parameters
| Dose |
Tmax |
Cmax |
AUC0-240h |
||||||
|---|---|---|---|---|---|---|---|---|---|
| Sex | Group | n | (mg/kg) | Day | (h) | (µg/mL) | (haµg/mL) | AIobs | Male/female ratio |
| Male | 2 | 3 | 30 | 1 | 0.5 | 842 | 78,400 | ||
| 21 | 0.5 | 1,180 | 146,000 | 1.9 | |||||
| 3 | 3 | 100 | 1 | 0.5 | 2,680 | 266,000 | |||
| 21 | 0.5 | 4,230 | 484,000 | 1.8 | |||||
| 4 | 5 | 300 | 1 | 0.5 | 7,750 | 824,000 | |||
| 21 | 1.6 | 11,300 | 1,350,000 | 1.6 | |||||
| 5a | 5 | 600 | 1 | 7.4 | 23,800 | 2,400,000 | |||
| 21 | 11 | 29,800 | 3,860,000 | 1.6 | |||||
| Female | 2 | 3 | 30b | 1 | 0.5 | 489 | 61,700 | NR | |
| 30 | 21 | 0.5 | 1,060 | 139,000 | NR | NR | |||
| 3 | 3 | 100 | 1 | 0.5 | 2,190 | 250,000 | 1.1 | ||
| 21 | 0.5 | 3,730 | 463,000 | 1.9 | 1.0 | ||||
| 4 | 5 | 300 | 1 | 0.5 | 7,290 | 823,000 | 1.0 | ||
| 21 | 0.5 | 10,900 | 1,360,000 | 1.7 | 1.0 | ||||
| 5a | 5 | 600 | 1 | 0.5 | 14,400 | 1,680,000 | 0.7 | ||
| 21 | 10 | 19,200 | 2,490,000 | 1.5 | 0.6 |
Tmax: time at maximum concentration; Cmax: maximum observed concentration; AUC0-240h: area under the concentration-time curve from hour 0 to 240 hours; AIobs: Accumulation index observed from single dose to Day 21.NR: No result given due to suspected error in the dosing solution
a600 mg/kg was assessed in a separate study
bAn error in dose level was suspected based on dosing solution analysis.