Input parameters for the PerMCL of the refined tizanidine PBPK model
fuEW and fuIW are the unbound fractions of the drug in extracellular and intracellular compartments, respectively. For the tizanidine-ciprofloxacin DDI, study specific CYP1A2 CLint values of 5.5, 5.2, and 4.7 μl/min/pmol were used in the simulation to recover observed tizanidine AUC in the control arm of the clinical study when CLPD,in vitro was 0.2, 0.25, and 0.5, respectively. The simulations for DDI with the other perpetrators were performed using the global (default) CYP1A2 CLint.
| Parameter | Value | Method/Reference |
|---|---|---|
| CLPD,in vitro (ml/min/million hepatocytes) | 0.2, 0.25, and 0.5 | Optimized to approximate the DM with a DN of 0.4, 0.3, and 0.2, respectively |
| CYP1A2 CLint (μl/min/pmol) | 3.9, 3.8, and 3.5 | Optimized based on clinical study when CLPD,in vitro was 0.2, 0.25, and 0.5, respectively |
| fuIW | 0.026 | Predicted by Rodgers and Rowland method (Rodgers and Rowland, 2006) |
| fuEW | 1.0 | Predicted by Rodgers and Rowland method (Rodgers and Rowland, 2006) |