Table II.
Mechanistic T-DM1 PK Model Parameter Estimates
| Rat | Cynomolgus monkey | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Parameter | Description | Unit | Value | RSE (%) | IIV (%) | RSE (%) | Value | RSE (%) | IIV (%) | RSE (%) |
| CLTT a | Total trastuzumab clearance | mL/day | 2.42 | (5.7) | 24.0 | (18) | 17.4 | (13) | 24.8 | (22) |
| k plasma | Plasma degradation rate constant | day−1 | 0.156 | (1.2) | – | – | 0.0939 | (3.0) | – | – |
| CL in vivo b | In vivo antibody clearance | mL/day | 0.704 | – | – | – | 3.50 | – | – | – |
| V 1 | Central volume | mL | 11.0 | (4.3) | 18.5 | (11) | 148 | (4.8) | 11.7 | (12) |
| CLd2 | Distributional clearance 2 | mL/day | 49.0 | (35) | – | – | 25.5 | (35) | – | – |
| V 2 | Peripheral volume 2 | mL | 3.44 | (58) | 49.4 | (41) | 57.2 | (38) | 46.8 | (33) |
| CLd3 | Distributional clearance 3 | mL/day | 12.0 | (16) | – | – | 81.2 | (19) | – | – |
| V 3 | Peripheral volume 3 | mL | 16.7 | (6.2) | 16.8 | (21) | 127 | (15) | – | – |
| k 7 → 6 c | DAR7–DAR3 deconjugation rate constants | day−1 | 0.543 | (15) | 21.8 | (40) | 0.341 | (7.7) | – | – |
| k 6 → 5 | ||||||||||
| k 5 → 4 | ||||||||||
| k 4 → 3 | ||||||||||
| k 3 → 2 | ||||||||||
| k 2 → 1 | DAR2 deconjugation rate constant | day−1 | 0.388 | (7.1) | – | – | 0.255 | (6.7) | – | – |
| k 1 → 0 | DAR1 deconjugation rate constant | day−1 | 0.114 | (30) | 15.1 | (48) | 0.0939 | (5.8) | – | – |
| Res err | Residual error | % | 11.1 | (6.1) | – | – | 15.3 | (3.3) | – | – |
T-DM1 trastuzumab emtansine, PK pharmacokinetic, IIV interindividual variability, RSE relative standard error
aComposed of CLin vivo and k plasma × V 1
bDerived by: CLin vivo = CLtrastuzumab − k plasma × V 1
cRate constants were determined to be equal from model building