Input parameters for the initial tizanidine PBPK model with the well stirred model
| Parameter | Value | Method/Reference |
|---|---|---|
| Molecular weight (g/mol) | 253.7 | PubChem |
| log Po:w | 1.84 | Average of 5 in silico estimates |
| Compound type | Monoprotic base | |
| pKa | 7.46 | FDA review (NDA 21-447) |
| BP | 1.46 | Predicted with Simcyp V21R1 |
| fu,p | 0.7 | (Shanker et al., 2009; Lombardo et al., 2018) |
| Main plasma binding protein | Human Serum Albumin | Assumed |
| Absorption model | First order absorption model | |
| Ptrans,0 (10−6 cm/s) | 249 | Predicted based on Log Po:w (Sugano, 2009) |
| Peff,human (10−4 cm/s) | 2.31 | Predicted using MechPeff model (Sugano, 2009; Pade et al., 2017) |
| fa | 0.94 | Predicted using Simcyp V21R1 |
| ka (1/h) | 1.01 | Predicted using Simcyp V21R1 |
| Lag time (h) | 0.5 | Reported upper limit of lag time for tizanidine tablets (FDA review, NDA 21-447) |
| fugut | 1 | Assumed |
| Qgut (L/h) | 10.88 | Predicted using Simcyp V21R1 |
| Distribution model | Full PBPK model | |
| VSS (L/kg) | 2.42 | Predicted by Method 2 (Rodgers and Rowland, 2006) with a Kp scalar (0.28) to recover clinically observed Vss |
| CYP1A2 CLint (μl/min/pmol) | 6.76 | Optimized based on clinical studya |
| Renal Clearance (L/h) | 3.4 | Clinical observations |
BP, blood-to-plasma ratio; fa, fraction absorbed; fugut, unbound fraction in gut enterocyte; fu,p, unbound fraction in human plasma protein; Kp, tissue: plasma partition coefficient; ka, first order absorption rate constant; Peff,human, effective permeability in human jejunum; Po:w, neutral species octanol: buffer partition coefficient; Ptrans,0, intrinsic transcellular passive permeability; pKa, the negative base-10 logarithm of the acid dissociation constant; Qgut, a nominal flow in the gut model; Vss, volume of distribution at steady state.
aFor the tizanidine-ciprofloxacin DDI, study specific CYP1A2 CLint of 11.4 μl/min/pmol was used in the simulation to recover the observed tizanidine AUC in the control arm of the clinical study. The simulations for DDIs with the other perpetrators were performed using the global (default) CYP1A2 CLint of 6.76 μl/min/pmol.