Table 3.
SimCYP PBPK input parameters.
| Adult Model | References | |
|---|---|---|
| Population | Healthy Volunteers | |
| Drug parameters | ||
| Physicochemical properties | ||
| Molecular weight (g/mol) | 804.02 | [36] |
| Log Po:w | 3.26 | [36] |
| Compound type | neutral | [36] |
| Blood binding | ||
| Concentration-dependent B/P profile | ||
| Bmax (E:P) | 80 | [2] |
| KD (µM) | 0.004726 | [2] |
| Fraction unbound in plasma (%) | 1.2 | [37] |
| Absorption | ||
| ADAM model | ||
| Peff (10−4 cm/s) | 4.77 | [26] |
| DLM model intrinsic solubility (mg/mL) | 0.06257 | Aqueous buffer solubility for tacrolimus formulation |
| Logarithm of bile micelle:buffer partitioning coefficient (log Km:w) |
4.55 | Fitted using SIVA based on solubility data in acetate buffer, ½ FaSSIF, FaSSIF and FeSSIF |
| Monodispersed particle size distribution radius (µm) | 10 | Default SimCYP value |
| Distribution | ||
| Distribution model | Minimal PBPK | |
| kin (1/h) | 0.68 | [16] |
| kout (1/h) | 0.12 | Fitted based on IV data [25] |
| Vsac (L/kg) | 5.5 | Fitted based on IV data [25] |
| Kp scalar | 10 | Fitted based on IV data [25] |
| Predicted Vss (L/kg) | 9.68 | Predicted in SimCYP |
| Prediction method | Method 2 | |
| Elimination | ||
| Pathway 1 | ||
| CYP3A4 | ||
| Vmax (pmol/min/pmol CYP) | 8 | [1] |
| Km,u (µM) | 0.21 | [1] |
| CYP3A5 | ||
| Vmax (pmol/min/pmol CYP) | 17 | [1] |
| Km,u (µM) | 0.21 | [1] |
| Pathway 2 | ||
| CYP3A4 | ||
| Vmax (pmol/min/pmol CYP) | 0.6 | [1] |
| Km,u (µM) | 0.29 | [1] |
| CYP3A5 | ||
| Vmax (pmol/min/pmol CYP) | 1.4 | [1] |
| Km,u (µM) | 0.35 | [1] |
Bmax = maximum E:P ratio, KD = constant of the drug–erythrocyte complex, Peff = effective permeability, Kin = rate constant into the single-adjusting compartment, Kout = rate constant out of the single-adjusting compartment, VSac = volume of the single-adjusting compartment, KP scalar = scalar for all tissue partition coefficients, VSS = volume of distribution at steady-state, Km,u = unbound Michaelis–Menten constant.