Table 1. Results from the sensitivity analysis.
The values are the Partial Ranked Correlation Coefficients (PRCC) for the given model parameters. Red shading indicates PRCC≤−0.4 and green shading indicates PRCC≥0.4. Results are based on 5000 LHS with the parameters varied ±100×baseline. Model outputs include AUC (0 to 8 hrs) and Cmin (concentration at 8 hrs).
| Parameter | Plasma | Liver | |||
|---|---|---|---|---|---|
| Sorafenib | Sorafenib N-oxide | Sorafenib Glucuronide | Sorafenib | Sorafenib Glucuronide | |
| AUC | |||||
| Sorafenib | |||||
| Intestinal permeability | 0.66 | 0.63 | 0.50 | 0.71 | 0.64 |
| Fraction unbound in plasma | −0.94 | 0.14 | 0.10 | 0.10 | 0.12 |
| Influx Activity | −0.87 | 0.34 | 0.22 | 0.34 | 0.31 |
| Abcc2 Activity | −0.03 | −0.04 | −0.02 | −0.05 | −0.04 |
| Abcc3 Activity | 0.03 | 0.01 | 0.00 | 0.02 | 0.02 |
| CYP3A4 Vmax | −0.36 | 0.92 | −0.20 | −0.44 | −0.33 |
| UGT1A9 Vmax | −0.84 | −0.81 | 0.65 | −0.89 | 0.80 |
| Sorafenib Glucuronide | |||||
| Intestinal permeability | −0.03 | −0.02 | 0.25 | −0.01 | 0.08 |
| Fraction unbound in plasma | 0.00 | 0.01 | −0.85 | 0.00 | −0.02 |
| Abcc2 Activity | 0.01 | 0.00 | −0.80 | 0.01 | −0.93 |
| Abcc3 Activity | 0.01 | 0.00 | 0.55 | 0.00 | 0.00 |
| Oatp1a/1b Activity | 0.01 | 0.01 | −0.84 | 0.01 | 0.02 |
| Non-specific hepatic loss | −0.01 | −0.01 | −0.25 | −0.01 | −0.38 |
| β-glucuronidase | 0.03 | 0.02 | −0.03 | 0.04 | 0.01 |
| Sorafenib N-oxide | |||||
| Non-specific hepatic loss | 0.01 | −0.92 | −0.02 | 0.01 | 0.00 |
| Other | |||||
| EHC continuous fraction | 0.05 | 0.04 | 0.23 | 0.07 | 0.15 |
| Parameter | Plasma | Liver | |||
|---|---|---|---|---|---|
| Sorafenib | Sorafenib N-oxide | Sorafenib Glucuronide | Sorafenib | Sorafenib Glucuronide | |
| Cmin | |||||
| Sorafenib | |||||
| Intestinal permeability | −0.07 | 0.16 | 0.08 | −0.01 | −0.03 |
| Fraction unbound in plasma | −0.79 | −0.01 | 0.00 | −0.11 | −0.05 |
| Influx Activity | −0.82 | −0.18 | −0.16 | −0.42 | −0.31 |
| Abcc2 Activity | −0.03 | −0.05 | −0.02 | −0.05 | −0.04 |
| Abcc3 Activity | 0.03 | 0.00 | 0.01 | 0.01 | 0.02 |
| CYP3A4 Vmax | −0.45 | 0.78 | −0.32 | −0.57 | −0.43 |
| UGT1A9 Vmax | −0.87 | −0.86 | −0.03 | −0.91 | −0.27 |
| Sorafenib Glucuronide | |||||
| Intestinal permeability | −0.06 | −0.04 | 0.20 | −0.06 | 0.06 |
| Fraction unbound in plasma | 0.01 | 0.00 | −0.59 | 0.00 | 0.00 |
| Abcc2 Activity | 0.03 | 0.02 | −0.69 | 0.03 | −0.82 |
| Abcc3 Activity | 0.01 | −0.01 | 0.41 | −0.01 | 0.04 |
| Oatp1a/1b Activity | −0.01 | 0.01 | −0.73 | 0.00 | −0.04 |
| Non-specific hepatic loss | −0.05 | −0.03 | −0.26 | −0.05 | −0.32 |
| β-glucuronidase | 0.09 | 0.07 | −0.06 | 0.09 | 0.01 |
| Sorafenib N-oxide | |||||
| Non-specific hepatic loss | 0.02 | −0.92 | −0.03 | 0.02 | 0.00 |
| Other | |||||
| EHC continuous fraction | 0.16 | 0.11 | 0.37 | 0.18 | 0.31 |