TABLE 1.
Input parameter values used to simulate the kinetics of trazodone
| Parameter name | Value | Method/source |
|---|---|---|
| Physical chemistry and blood binding | ||
| MW, g/mol | 408.32 | 5 |
| Log P | 2.87 | Calculated from experimental value of logD7.4 (=2.79) 1 |
| Compound type | Monoprotic base | 1 |
| pK a | 6.61 | Measured 1 |
| B/P | 0.68 | Calculated from measured E:P ratio of 0.2 (data on file) |
| fup | 0.0354 | Measured by equilibrium dialysis (data on file) |
| Absorption | ||
| Model |
IR: first order OAD: ADAM with Solid Monolithic /Dissolution Profile Input (Table S1) |
|
| F a | IR: 0.98 | Predicted from mean Papp (24.2 * 10−6 cm/s) obtained in Caco‐2 cells and calibrated using metoprolol data (28.1 * 10−6 cm/s) 10 |
| k a (h−1) |
IR/oral solution: 1.60 OAD: 0.07 |
IR: Predicted from mean Papp (24.2 * 10−6 cm/s) obtained in Caco‐2 cells and calibrated using metoprolol data (28.1 * 10−6 cm/s) 10 OAD: fitting of concentration‐time data following a single oral dose of 300 mg OAD trazodone 16 |
| fugut | 1.0 | Default value |
| Distribution | ||
| Model | Full‐PBPK | |
| V ss (L/kg) | 1.0 | Predicted (Method 2) 17 |
| Elimination | ||
| CLiv (L/h) | 5 | 18 |
| f m,CYP3A4 (%) | 100 | |
Abbreviations: ADAM, Advanced Dissolution Absorption and Metabolism; IR, immediate release; MW, molecular weight; OAD, once a day; PBPK, physiologically‐based pharmacokinetic; Vss, volume of distribution at steady state.