Table 1.
Values of physicochemical and pharmacokinetic parameters used in the PBB modelling for diclofenac.
| Parameter (units) | Values used | References/comments |
|---|---|---|
| Physicochemical and blood binding parameters | ||
| Molecular weight (g/mol) | 296.15 | |
| Log Po:w | 4.4 | (Chuasuwan et al., 2009) |
| Compound type | Monoprotic acid | (Chuasuwan et al., 2009) |
| pKa | 3.8 | (Chuasuwan et al., 2009) |
| Fraction unbound in plasma | 0.003 | (Accord-UK Ltd, 2018) |
| Blood plasma ratio | 0.7 | .(Tang et al., 1999) |
| Fraction unbound in enterocyte | 1 | Simcyp compound file |
| Drug absorption parameters (ADAM model) | ||
| MechPeff Model Ptrans,0 (10−6 cm/s) | 440,108.3 | Predicted using physicochemical properties |
| Predicted Peff,man (x10−4 cm/s) | 3.89 (duodenum), 10.06 (jejunum I), 7.05 (jejunum II), 1.65 (Ileum I), 1.65 (Ileum II), 1.62 (Ileum III), 1.56 (Ileum IV), 0.85 (colon) | Predicted in Simcyp using Mechpeff Model |
| Aqueous intrinsic solubility (mg/mL) | 0.0018 | Calculated used pH solubility profile (Guhmann et al., 2013) |
| Solubility factor | 546.20 | Estimated in Simcyp |
| Particle density (g/mL) | 1.2 | Default Simcyp Value |
| Particle size distribution | Monodispersed | Default Simcyp Value |
| Particle radius (µm) | 10 | Default Simcyp Value |
| Log bile micellar: buffer partition coefficient (Log Km:w) neutral | 5.91 | Estimated in SIVA |
| Log Km:w ion | 0.00038 | Estimated in SIVA |
| Particle diffusion layer thickness (heff) prediction | Hintz-Johnson method | |
| Monomer diffusion coefficient (10−4 cm2/min) | 4.73 | Predicted in Simcyp |
| Micelle diffusion coefficient (10−4 cm2/min) | 0.78 | Default Simcyp value |
| Diffusion layer model (DLM) Scalar (tablet formulation) | 31.13 | Estimated in SIVA from Erweka mini-paddle dissolution experiment |
| Disintegration Model | First order | |
| Maximum% fraction of drug dose dissolved | 100 | Estimated in SIVA from Erweka mini-paddle dissolution experiment |
| Kd1 | 0.17 | |
| Lag (min) | 7.43 | |
| Distribution parameters | ||
| Model | Minimal PBPK model | |
| kin (1/h) | 1.88 | Estimated using IV data |
| kout (1/h) | 1.48 | Estimated using IV data |
| Vsac (L/kg) | 0.11 | Estimated using IV data |
| Method | Method 2 | |
| Tissue-plasma partition coefficient (Kp) scalar | 2 | (Davies and Anderson, 1997) |
| Steady State Volume of Distribution (Vss) (L/kg) | 0.15 | Predicted within Simcyp |
| Elimination parameters | ||
| Intravenous clearance (CLiv) (L/h) | 21.50 | Estimated using IV data |
| Renal clearance (L/h) | 0.00036 | (Rowland and Tozer, 1995) |
| Population parameters | ||
| Stomach Mean residence time (h) | 0.27 (Tablet) / 0.05 (Solution) | |