Simcyp input parameters for TBPT, M1, and M2
| Parameter | TBPT | M1 | M2 | Source |
|---|---|---|---|---|
| Molecular weight (g/mol) | 432 | 318 | 430 | Calculatede |
| Log P | 1.68 | 2.19 | 2.08 | Calculatede |
| Compound type | Monoprotic base | Monoprotic base | Monoprotic base | |
| pKa | 8.8 | 10.22 | 6.48 | Calculatede |
| B/P | 0.86 | 0.88 | 0.55a | Measured |
| fu,p | 0.38 | 0.64 | 0.0025 | Measured |
| Absorption | ||||
| Model | First order | NA | NA | |
| Fraction absorbed | 1 | NA | NA | Assumed |
| ka (1/h) | 0.6 | NA | NA | Fitting |
| fu (gut) | 1 | 1 | 1 | Assumed |
| Manin-Darby Canine Kidney Cell Permeability (10−6 cm/s) | 23 | NA | NA | Measured |
| Distribution | ||||
| Model | Minimal PBPK | Minimal PBPK | Minimal PBPK | |
| Vss (l/kg) | 2.1b | 1.64c | 0.26c | Fitting |
| Elimination | ||||
| 3A4 CLint (µl/min/mg) (forming M1) | 12 or 13d | Measured | ||
| 3A4 CLint (µl/min/mg) (forming M2) | 2.5 or 13d | Measured | ||
| Additional HLM CLint (µl/min/mg) | 17.5 or 6 | 32 | 102 | Measured |
B/P, blood-to-plasma ratio.
↵a Minimum value for Simcyp is 0.55; measured value was 0.53.
↵b Predicted using dog PK data.
↵c Value from Simcyp using method 1.
↵d CLint values represent measured values and measured values multiplied by factors of 1.1 and 5.2 for M1 and M2, respectively, to account for secondary metabolism.
↵e Calculated using ACD/Labs Software (Advanced Chemistry Software, Toronto, Ontario, Canada).