Table 5.
Predicted and observed PK parameters (mean and standard error on the mean (SEE)in %)
| Plasma pharmacokinetics: distribution clearance from central to peripheral compartments central volume of distribution | |||
|---|---|---|---|
| Monkey | Humans | ||
| model A | scaled model A§ | model B | |
| Estimated | Predicted | Estimated | |
| Parameters | Mean (SEE%) | Mean (SEE%) | Mean (SEE%) |
| Central Vd (l) | 0.418 (12) | 6.27 | 4.09 (9) |
| Distribution clearance 1* (l h−1) | 0.167 (6) | 2.51 | 2.54 (4) |
| Distribution clearance 2* (l h−1) | 0.0043 (25) | 0.0648 | 0.0608 (30) |
| Distribution clearance 3* (l h−1) | 1.67 (24) | ||
| Peripheral (tissue) pharmacokinetics: elimination clearance and peripheral volumes of distribution | |||
|---|---|---|---|
| Monkey | Humans | ||
| model A | scaled model A§ | model B | |
| Estimated | Predicted | Estimated | |
| Parameters | Mean (SEE%) | Mean (SEE%) | Mean (SEE%) |
| Peripheral Vd 1† (l) | 1195 (22) | 17925 | 25900 (16) |
| Peripheral Vd 2† (l) | 0.13 (54) | 1.97 | 0.936 (23) |
| Peripheral Vd 3† (l) | 2.51 (12) | ||
| Elimination clearance (l h−1) | 3.45 (15) | 51.8 | 23.1 (48) |
| Terminal half-life‡ (days) | 9 | 9 | 32.7 (22–52) |
*
Distribution clearance 1, 2 and 3 = LY2181308 distribution from central compartment to first (low uptake tissue) and second/third (high uptake tissue) peripheral compartments, respectively.
†
Peripheral volumes of distribution.
‡
derived from the model parameters (mean and range).
§
Assuming weight of 5 kg monkey and 75 kg human.