Table 4.
Pharmacokinetic parameters for total antibody (TA), binding antibody (BA) and free MMAE(FA) at different dose levels
| Single dose | Multiple dose | ||||||
|---|---|---|---|---|---|---|---|
| PK parameters | 0.1 mg/kg N = 1 |
0.5 mg/kg N = 1 |
1.0 mg/kg N = 3 |
2.0 mg/kg N = 6 |
2.5 mg/kg N = 11 |
3.0 mg/kg N = 3 |
2.5 mg/kg N = 11 |
| Cmax (ng/mL) | |||||||
| TA | 697 | 4.2E3 | 1.3E4 (4.0E3) | 4.5E4 (6.2E4) | 5.6E4 (2.4E4) | 7.8E4 (4.3E4) | 4.1E4 (1.1E4) |
| BA | 677 | 9.5E3 | 1.3E4 (2.1E3) | 3.8E4 (3.6E4) | 5.3E4 (2.6E4) | 5.2E4 (1.8E4) | 3.7E4 (6164) |
| FM | NA | 1 | 2 (1) | 5 (4) | 6 (2) | 13 (4) | 6 (4) |
| AUC0−t (h*ng/mL) | |||||||
| TA | 7.0E3 | 1.2E5 | 2.6E5 (4.4E4) | 1.3E6 (4.1E5) | 1.9E6 (5.6E5) | 2.3E6 (6.1E5) | 1.9E6 (6.3E5) |
| BA | 6.0E3 | 1.3E5 | 2.0E5 (6.0E4) | 7.3E5 (2.6E6) | 1.1E6 (2.7E5) | 1.2E6 (2.9E5) | 1.0E6 (9.5E4) |
| FM | NA | 118 | 356 (233) | 746 (521) | 912 (440) | 2.4E3 (672) | 865 (251) |
| AUC0−inf (h*ng/mL) | |||||||
| TA | 8.5E3 | 1.2E5 | 2.6E5 (4.3E4) | 1.4E6 (4.2E5) | 1.9E6 (5.8E5) | 2.3E6 (6.2E5) | 2.0E6 (4.9E5) |
| BA | 6.7E3 | 1.4E5 | 2.1E5 (6.1E4) | 7.4E5 (2.6E5) | 1.1E6 (2.6E5) | 1.2E6 (2.9E5) | 1.2E6 (2.3E5) |
| FM | NA | 133 | 376 (237) | 850 (664) | 990 (551) | 2.0E3 (206) | 896 (210) |
| Tmax (h) | |||||||
| TA | 0.58 | 0.65 | 1.52 (1.03–1.52) | 1.48 (1.02–1.53) | 1.08 (0.2–1.53) | 1.5 (1.07–1.55) | 1.14 (1.03–1.5) |
| BA | 0.58 | 0.65 | 1.52 (1.03–1.52) | 1.10 (1.02–1.47) | 1.08 (0.2–1.53) | 1.5 (1.07–1.55) | 1.48 (1.17–1.53) |
| FM | NA | 47.98 | 48.25 (48.15–72) | 48.06 (23.95–71.67) | 71.67 (47.18–119.6) | 47.18 (46.87–119.07) | 47.15 (22.6–71.6) |
| t1/2z (h) | |||||||
| TA | 9.6 | 12.5 | 15.9 (2.5) | 33.9 (8.6) | 36.8 (9.2) | 42.2 (0.4) | 44.1 (12.4) |
| BA | 7.2 | 22.0 | 16.2 (9.5) | 33.2 (11.6) | 45.7 (17.6) | 45.5 (8.3) | 103.1 (93.7) |
| FM | NA | 44.8 | 63.8 (12.7) | 68.6 (46.8) | 61.3 (18.0) | 38.3 (15.5) | 81.3 (27.7) |
| Vz (mL/kg) | |||||||
| TA | 163.5 | 73.6 | 87.0 (10.9) | 76.0 (23.9) | 72.4 (14.7) | 82.4 (19.9) | 86.8 (46.1) |
| BA | 154.7 | 115.2 | 108.8 (54.7) | 150.3 (81.9) | 158.5 (80.4) | 170.7 (65.9) | 340.8 (299.6) |
| FM | NA | 2.4E5 | 4.0E5 (3.7E5) | 3.1E5 (2.0E5) | 2.6E5 (1.1E5) | 8.0E4 (2.5E4) | 4.1E5 (2.5E5) |
| CLz (mL/h/kg) | |||||||
| TA | 11.8 | 4.1 | 3.8 (0.6) | 1.6 (0.5) | 1.4 (0.4) | 1.4 (0.3) | 1.3 (0.3) |
| BA | 14.9 | 3.6 | 5.2 (1.7) | 3.2 (1.6) | 2.3 (0.5) | 2.6 (0.7) | 2.4 (0.2) |
| FM | NA | 3762.4 | 4.4E3 (4.2E3) | 3.5E3 (2.0E3) | 3.2E3 (1.4E3) | 1.5E3 (151.4) | 3.3E3 (1.1E3) |
TA toal antibody, BA binding antibody, FM free MMAE