Table IV.
Parameters for Model Drugs in Non-Pregnant and Pregnant PBPK Model. Parameter Values Used in the Pregnancy PBPK Model are in Italics (e.g., Nonpregnant Parameter Values → Late Pregnant parameter values)
| Parameters | Metformin | Digoxin | Midazolam | Emtricitabine |
|---|---|---|---|---|
| Basic compound/formulation Information | ||||
| Dose (mg) | 500 | 0.25 | 2 | 200 |
| Dosing regimen | Twice daily | Single dose | Single dose | Once daily |
| Main clearance pathways | Renal | Renal (∼60%) | Hepatic (CYP3A4) | Renal |
| Formulations | IR tablet | IR tableta | IR tableta | IR capsulea |
| Gut physiology | Fasted | Fasteda | Fasteda | Fasteda |
| Parameters not influenced by pregnancy (e.g., physicochemical properties) | ||||
| Acid/base | Base | Neutral | Base | Base |
| MW (g/mol) | 129.2 | 781 | 325.8 | 247.3 |
| Log D at pH 7.4 | −1.386 | −1.4 | 3.56 | −0.43 |
| pK a | 10.37 | 12.98 | 5.5 | 2.65 |
| Solubility in water (mg/mL) | 129 | 0.25 | 0.024 | 112 |
| Effective permeability (10−4 cm/s) | 0.25 | 1.02 | 6.28 | 2.00 |
| Diffusion Coefficients (cm2/s) | 1.21 | 0.439 | 0.856 | 0.75 |
| Blood-to-plasma ratio | 0.7 | 1.1 | 0.55 | 1 |
| BCS/BDDCS Class | 3 | 3 | 1 | 1 |
| Parameters influenced by pregnancy (e.g., disposition parameters) | ||||
| Fraction unbound in plasma (f up, %) | 100 → 100 | 63 → 67 | 0.61 → 0.71 | 96 → 96 |
| V ss predicted by PBPK (L) | 82.7 → 101 b | 643 → 872 b | 85.8 → 125 b | 156 → 210 b |
| 100 c | 845 c | 120 c | 191 c | |
| Gut FPE (%) | 0 | 0 | 40 → 54 | 0 |
| Hepatic CL (L/h) | 0 | 4.2 → 4.2 | 24.5 → 33.1 | 0 |
| Renal CL (L/h) | 28.5 → 40.0 | 6.9 → 10.2 | N/A | 19.1 → 26.6 |
| GFR (L/h) | 9.9 → 13.8 | 7.4 → 10.5 | N/A | 6.8 → 9.4 |
| Filtration CL (L/h) | 9.9 → 13.8 | 4.6 → 7.01 | N/A | 6.6 → 9.1 |
| Secretion CL (L/h) | 18.7 → 26.2 | 2.3 → 3.11 | N/A | 12.5 → 17.6 |
aThe corresponding information is not available and was assumed
b V ss predicted by model 1
c V ss predicted by model 2