Comparison of predicted FG and apparent intravenous and oral clearance data for 12 drugs and observed data
Predictions were performed using either the QGut or PBPK modeling approach.
| Observed | Predicted | ||||||
|---|---|---|---|---|---|---|---|
| FGa | CLi.v.a | CLorala | FG (QGut)b | FG (PBPK)b | CLi.v.b | CLoralb | |
| l/h | l/h | ||||||
| Atorvastatin | 0.38c | 37.5 | 949 | 0.90 | 0.90 | 9.05d | 12.0d |
| Buspirone | 0.21 | 119 | 4910 | 0.69 | 0.73 | 29.7 | 70.6 |
| Cyclosporine | |||||||
| Neoral | 0.44 | 16.8e | 51.7e | 0.85 | 0.92 | 3.71e | 17.1e (Fa = 24%) |
| Sandimmune | 0.44 | 16.8e | 107e | 0.85 | 0.92 | 3.70e | 24.6e (Fa = 16%) |
| Felodipine | 0.45 | 50.0 | 462 | 0.21 | 0.20 | 22.5 | 254 |
| Indinavir | 0.93 | 77.3 | 59.6 | 0.31 | 0.98 | 82.0 | 547 (Fa = 61%) |
| Lovastatin | 0.07 | 1380 | 0.11 | 0.10 | 45.9 | 4110 | |
| Midazolam | 0.51 | 25.9 | 102 | 0.54 | 0.53 | 24.7 | 150 |
| Nisoldipine | 0.11 | 60.5 | 1340 | 0.08 | 0.08 | 49.0 | 1990 |
| Saquinavir | 0.18 | 54.2 | 14,400 | 0.02 | 0.56f | 65.6 | 3620f (Fa = 41%) |
| Simvastatin | 0.14 | 1630 | 0.07 | 0.07 | 48.0 | 6320 | |
| Tacrolimus | 0.14 | 2.69e | 20.7e | 0.28 | 0.28 | 1.36e | 8.79e |
| Terfenadine | 0.40 | 5290 | 0.11 | 0.32 | 76.9 | 2720 (Fa = 52%) | |
a Summary from Gertz et al. (2010).
b Predictions were performed using the clearance data from HIM and HLM and apparent permeability data determined in MDCK-MDR1 cells reported previously (Gertz et al., 2010).
c Reassessed from the intravenous clearance data provided in Lennernäs (2003) and Rb value of 0.61 (see Materials and Methods).
d Acid-lactone conversion was not considered. Predictions based on 70-fold higher intrinsic clearance values of the lactone (Jacobsen et al., 2000) resulted in apparent intravenous and oral clearance values of 54.4 and 786 l/h, respectively.
e Apparent blood clearance values.
f Absorption in the proximal colon (Agoram et al., 2001) was incorporated in the current model.