Table 5.
Mean (SD) toxicokinetic parameters of AMG 181 after repeated i.v. or s.c. administrations in male and female cynomolgus monkeys
| Study | Regimen (weekly dosing) | Week | n | tmax (h) | Cmax (μg·mL−1) | AUC0-t (μg·h·mL−1) | AR |
|---|---|---|---|---|---|---|---|
| Two-dose non-GLP | 0.5 mg·kg−1 s.c. | 1 | 8 | 72 (24–72) | 6.92 (0.594) | 962 (88.8) | NC |
| ×2 | 2 | 8 | 72 (24–72) | 10.4 (1.73) | NC | NC | |
| 80 mg·kg−1 s.c. | 1 | 8 | 72 (24–72) | 1010 (60.1) | 143 000 (7 440) | NC | |
| ×2 | 2 | 7–8 | 72 (24–72) | 1610 (117) | 245 000 (23 800) | 1.70 (0.119) | |
| 3 month GLP | 5 mg·kg−1 s.c. | 1 | 12 | 72 (24–168) | 69.6 (5.8) | 10 000 (826) | NC |
| ×13 | 13 | 1 | NC | NC | NC | NC | |
| 20 mg·kg−1 s.c. | 1 | 12 | 72 (24–72) | 279 (34.5) | 39 700 (4 680) | NC | |
| ×13 | 13 | 10 | 24 (8–72) | 821 (164) | 109 000 (19 700) | 2.76 (0.634) | |
| 80 mg·kg−1 s.c. | 1 | 12 | 72 (24–72) | 1090 (72.8) | 158 000 (12 500) | NC | |
| ×13 | 13 | 12 | 24 (8–72) | 2990 (597) | 391 000 (80 500) | 2.48 (0.477) | |
| 80 mg·kg−1 i.v. | 1 | 11 | 0.25 (0.25–3) | 2410 (144) | 205 000 (18 000) | NC | |
| ×13 | 13 | 11 | 0.25 (0.25–24) | 4850 (606) | 485 000 (75 800) | 2.37 (0.405) |
All values are reported to three significant figures except for tmax, where values are reported to two decimal places for values <1.
tmax, time to Cmax after the reference dose 1 or 2 for the two-dose non-GLP study, and dose 1 or 13 for the 3 month GLP study; tmax values presented as median (min–max); Cmax, maximum observed concentration; AUC0-t, area under the concentration–time curve from time zero to the last observed concentration (within each dosing interval during week 1 or week 2 for the two-dose non-GLP study and week 1 or week 13 for the 3 month GLP study; AR, accumulation ratio; AUC0-t, week 2/AUC0-t, week 1 for the two-dose non-GLP study, and AUC0-t, week 13/AUC0-t, week 1 for the 3 month GLP study; NC, not calculated.