Table 3.
Values of physicochemical and pharmacokinetic parameters used in PBPK models for itraconazole in the present study.
| Parameter (Units) | Values Used | Refs/Comments |
|---|---|---|
| Physchem and Blood Binding Parameters | ||
| Mol wt (g/mol) | 704.64 | |
| Log Po:w | 5.66 | FDA Label Sporanox |
| Compound type | Monoprotic base | In house experimental database |
| pKa | 3.87 | In house experimental database |
| Fraction unbound in plasma | 0.002 | FDA Label Sporanox |
| Blood plasma ratio | 0.58 | Simcyp inhibitor compound file |
| Fraction unbound in enterocyte | 0.016 | Simcyp inhibitor compound file |
| Drug Absorption Parameters (ADAM Model) | ||
| MCDK II (×10−6 cm/s) | 57.1 | Simcyp inhibitor compound file |
| Calibrator compounds MCDK II permeability (×10−6 cm/s) | Cimetidine 2.00 Propranolol 49.60 Verapamil 59.10 |
Simcyp inhibitor compound file |
| PredictedPeff,man (×10−4 cm/s) | 9.85 | Predicted in Simcyp using MCDK cell permeability |
| Aq intrinsic solubility (mg/mL) | 8.94E-05 | Back calculated using pH solubility data |
| Solubility factor | 222.37 | Estimated in SIVA |
| DLM scalar | 1 | Simcyp default value |
| Particle density (g/mL) | 1.2 | Simcyp default value |
| Particle size distribution | Monodispersed | Simcyp default value |
| Particle radius (µm) | 10 | Simcyp default value |
| Log Km:w neutral | 5.62 | Predicted in SIVA |
| Log Km:w ion | 5.48 | Predicted in SIVA |
| Particle heff prediction | Hintz–Johnson method | Default Simcyp method [27] |
| CSR | 44.97 | Calculated from experimental data, this study |
| PRC (1/h) | 1.98 (OS), 2.11 (capsules) | Calculated from experimental data, this study |
| sPRC (1/h) | N/A | |
| Monomer diffusion coeff (10−4 cm2/s) | 3.17 | Predicted within Simcyp |
| Micelle diffusion coeff (10−4 cm2/s) | 0.78 | Default Simcyp Value |
| Solid state 2 (Capsules only) | ||
| Aq. intrinsic solubility (mg/ml) | 0.001 | Matsui et al. [32] |
| DLM scalar | 0.69 | Estimated in SIVA from dissolution profile |
| Excipient Mediated Solubility (OS only) | ||
| Binding constant (M−1) | 1654 (K1:1), 13 (K1:2) | Peeters et al. [33] |
| Binding constant (M−1) stomach | 9895 (K1:1), 23 (K1:2) | Peeters et al. [33] |
| Distribution Parameters | ||
| Model | Full PBPK Model | |
| Method | Method 2 | |
| Kp scalar | 0.19 | Poirier et al. [34] |
| Vss (L/kg) | 11.06 | Predicted within Simcyp |
| Elimination Parameters | ||
| CLiv (L/h) | 22.9 | Heykants et al. [21] |
| Renal clearance (L/h) | 0 | Simcyp inhibitor compound file |