Table 1.
PK and PD model variables of gefitinib determined in mice bearing intracerebral U87vIII tumors. A. Systemic PK parameters, B. Brain tumor PK parameters in regions corresponding to low (less intact BBB), medium and high MPI (more intact BBB) regions and C. PD model variables related to pERK inhibition. Values represent mean (% Coefficient of variation) of model fitted variables unless otherwise stated.
| A
| ||
|---|---|---|
| Variables | Units | Values |
| F | 0.50* | |
| Vc | ml | 69.41 (15%) |
| k10 | 1/hr | 0.31 (17%) |
| Ka | 1/hr | 0.88* |
| k2,1 | 1/hr | 0.26 (38%) |
| k1,2 | 1/hr | 0.30 (59%) |
| B
| ||||
|---|---|---|---|---|
| Variables | Units | High MPI group | Medium MPI group | low MPI group |
| Kp | ml/hr | 0.0024 (23%) | 0.0022 (18%) | 0.0012 (68%) |
| Km | ng/g | 2026.65 (10%) | 2048.51 (10%) | 2003.35 (10%) |
| Vmax | ng/hr | 20.07 (29%) | 18.27 (23%) | 6.47 (55%) |
| h | ml/hr | 0.0006 (63%) | 0.0009 (37%) | 0.005 (34%) |
| R* | - | 2 | 2 | 2 |
| Qt* | ml/hr | 3 | 3 | 3 |
| Vt* | ml | 0.001 | 0.001 | 0.001 |
| AUC high dose(0–24) | hr*ng/g | 1.68E+05 | 1.67E+05 | 1.70E+05 |
| AUC low dose(0–24) | hr*ng/g | 2.27E+04 | 2.54E+04 | 4.91E+04 |
| C
| |||
|---|---|---|---|
| Variables | Units | Value | |
|
| |||
| High Dose Model | Low Dose Model | ||
|
|
|||
| IC50 | ng/g | 41969.54 (44%) | 16073.65 (42%) |
| k* | 1/hr | 1 | 1 |
| Kin | 1/hr | 2.02 (11%) | 2.02* |
| kout | 1/hr | 2.58 (10%) | 2.74 (5%) |
| ktr | 1/hr | 0.32 (18%) | 1.34 (16%) |
| Predicted ABEC (High MPI group) | a | 9.53 | 7.57 |
| Predicted ABEC (Medium MPI group) | a | 9.48 | 7.64 |
| Predicted ABEC (Low MPI group) | a | 9.72 | 8.45 |
*
Values fixed either based on literature or experimentally determined values.
a
units of ABEC: (Fraction of baseline pERK * time (hr))
*
The parameter “k” was used to link gefitinib tumor concentrations to the pEGFR target compartment and fixed at a value of 1.