TABLE 1.
Parameter‐values used for PBPK/PD models of edoxaban and M4 in SimCYP.
| Parameter | Edoxaban | M4 |
|---|---|---|
| Physiochemical and blood binding | ||
| Molecular weight (g/mol) | 548.6 (DrugBank) | 521.0 |
| logP | 1.61 (DrugBank) | 1.68 (ACD) |
| Compound type | Monoprotic base | Monoprotic acid |
| pKa | 6.7 (DrugBank) | 4.09 (ACD) |
| Blood‐to‐plasma ratio | 0.96 17 | 0.96 (assumed to be the same as edoxaban) |
| f u | 0.45 (Drug label) | 0.2 4 |
| Absorption model | ADAM |
|---|---|
| f u, gut predicted | 0.24 |
| P eff,man type | Regional |
| P Caco‐2 (10−6 cm/s) | 10.3 6 |
| Input form | Solid formulation |
| Formulation | Immediate release (IR) |
| Total solubility in segment (mg/mL) | |
| Stomach | 4.40 17 |
| Duodenum | 1.80 17 |
| Jejunum | 0.54 17 |
| Ileum | 0.14 17 |
| Colon | 0.6 17 |
| Distribution model | Full PBPK model | Full PBPK model |
|---|---|---|
| V ss input type | Predicted using Method 1 | Predicted using Method 2 |
| V ss predicted (L/kg) | 1.04 | 0.16 |
| Tissue to plasma partition coefficients | ||
| Adipose | 1.30 | 0.06 |
| Skin | 1.08 | 0.35 |
| Gut | 1.47 | 0.22 |
| Liver | 1.30 | Permeability limited |
| Lungs | 0.68 | 0.28 |
| Heart | 0.84 | 0.22 |
| Kidneys | 1.02 | 0.20 |
| Spleen | 1.03 | 0.17 |
| Muscle | 1.01 | 0.10 |
| Bone | 1.64 | 0.13 |
| Brain | 1.78 | 0.11 |
| Elimination | ||
| CYP3A4 CLint (μL/min/mg protein) | 1.1 (See text) | |
| CES1 CLint (μL/min/mg protein) | 2.2, forms metabolite M4 | |
| Biliary CLint (μL/min/106) | 1.1 (See text) | 0.4 (Optimized) |
| Renal clearance (L/h) | 10.7 18 | 1 (Optimized) |
| Transporter kinetics | ||
| Intestines | ||
| P‐gp | ||
| J max (pmol/min) | 108 (See text) | |
| K m (μM) | 9.1 (See text) | |
| K i value of ketoconazole (μM) | 0.17 29 | |
| K i value of erythromycin (μM) | 1.1 (Optimized) | |
| Indmax value of rifampicin | 4.01 30 | |
| IndC50 value of rifampicin (μM) | 0.0639 30 | |
| Liver | ||
| CLPD (mL/min/106 cells) | 0.001 (See text) | |
| OATP1B1 | ||
| CLint,T (μL/min/106 cells) | 4.6 (See text) | |
| Scaling factor | 22 19 | |
| K i value of cyclosporine (μM) | 0.014 34 | |
| Indmax value of rifampicin | 2.23 31 | |
| IndC50 value of rifampicin (μM) | 0.0639 31 | |
| Pharmacodynamic | ||
| PD input type | Free concentration | Free concentration |
| PK/PD input compartment | Plasma | Plasma |
| Effect model | Linear | Linear |
| Slope for PT | 20 | 33 |
| Slope for aPTT | 56 | 93 |
| Baseline model | Additive | Additive |
Abbreviations: ADAM, Advanced Dissolution, Absorption and Metabolism; CLint, intrinsic clearance; f u, fraction of unbound drug in plasma; Indmax, maximal fold induction; J max, maximal flux value; K i, inhibition constant; K m, kinetic metabolite; PBPK, physiologically‐based pharmacokinetic; PD, pharmacodynamic; Peff, effective permeability; PK, pharmacokinetic; Vss, volume of distribution at steady state.