Table 5.
PK Parameters for SRK-181 in Sprague-Dawley Rats and Cynomolgus Monkeys From GLP Multidose TK Studies.
| Sprague-Dawley rats (male and female) | Number of animals = 6/sex/group | 30 mg/kga | 100 mg/kg | 200 mg/kg |
|---|---|---|---|---|
| Day 1 | Cmax (µg/mL) | 626 | 2,750 | 5,250 |
| Tmax (h) | 1 | 1 | 1 | |
| AUC0-168 (h*µg/mL) | 61,400 | 252,000 | 506,000 | |
| Day 22 | Cmax (µg/mL) | 1,310 | 4,640 | 9,980 |
| Tmax (h) | 1 | 1 | 1 | |
| AUC0-168 (h*µg/mL) | 162,000 | 559,000 | 1,010,000 | |
| CL (mL/h/kg) | 0.185 | 0.179 | 0.197 | |
| Day 29 | Cmax (µg/mL) | 1,570 | 5,410 | 9,730 |
| Tmax (h) | 1 | 1 | 1 | |
| AUC0-696 (h*µg/mL) | 477,000 | 1,550,000 | 2,910,000 | |
| t½ (h) | 322 | 393 | 356 | |
| CL (mL/h/kg) | 0.145 | 0.147 | 0.157 | |
| Vss (mL/kg) | 54.5 | 60.3 | 62.3 | |
| Cynomolgus monkeys (male and female) |
Number of animals = 4 or 6 /sex/group | 30 mg/kg | 100 mg/kg | 300 mg/kg |
| Day 1 | Cmax (µg/mL) | 688 | 2,290 | 6,470 |
| Tmax (h)b | 1.00 (1.00-1.00) | 1.00 (1.00-1.00) | 1.00 (1.00-1.00) | |
| AUC0-168 (h*µg/mL) | 61,900 | 217,000 | 641,000 | |
| Day 22 | Cmax (µg/mL) | 1,150 | 3,820 | 11,200 |
| Tmax (h)b | 1.00 (1.00-24.0) | 1.00 (1.00-48.0) | 1.00 (1.00-1.00) | |
| AUC0-168 (h*µg/mL) | 121,000 | 454,000 | 1,330,000 | |
| CL (mL/h/kg) | 0.259 | 0.226 | 0.233 | |
| Day 29 | Cmax (µg/mL) | NA | NA | 13,000 |
| Tmax (h)b | NA | NA | 1.00 (1.00-1.00) | |
| AUC0-168 (h*µg/mL) | NA | NA | 1,720,000 | |
| AUC0-696 (h*µg/mL) | NA | NA | 3,660,000 | |
| t½ (h) | NA | NA | 375 | |
| CL (mL/h/kg)c | NA | NA | 0.182 | |
| Vss (mL/kg)c | NA | NA | 69.9 |
Abbreviations: AUC0-168, area under the curve from time 0 to 168 hours; AUC0-696, AUC from 0 to 696 hours; CL, clearance; Cmax, maximum observed concentration; NA, not applicable; PK, pharmacokinetics; t½, elimination half-life; Tmax, time of maximum observed concentration; Vss, volume of distribution at steady state.
a On day 1, animals in 30 mg/kg group were administered approximately 70.0% of the nominal dose level (30 mg/kg/wk). The actual dose level of 21 mg/kg/wk was used to compensate for this event in TK analysis.
b Median (minimum-maximum) values are presented for Tmax.
c Due to the slow elimination relative to the dosing frequency on days 1 and 22, estimation of t½ and Vss was only attempted for recovery animals on day 29.