TABLE 1.
Input parameter for SVL and SVA models
| SVL | ||||
|---|---|---|---|---|
| Simcyp | PK‐Sim | |||
| Parameter | Value | Reference | Value | Reference |
| Molecular weight (g/mol) | 418.57 | Drug bank | 418.57 | Drug bank |
| f u —experimental | 0.017 | (26) | 0.017 | (26) |
| B:P—experimental | 0.57 | Internal database | 0.57 a | Internal database |
| LogPo:w | 4.68 | Drug bank | 4.68 | Drug bank |
| Compound type | Neutral | Drug bank | Neutral | Drug bank |
| Absorption | ||||
| P eff,man (cm/s) | 4.28 10−4 (ADAM) | Predicted based on in vitro Caco‐2 data | ||
| Specific intestinal permeability (cm/s) | 3.2 10−6 | Estimated (PE) | ||
| Formulation | ||||
| Input form | Solid IR | Tablet | ||
| Type of model | DLM | Weibull | ||
| Particle size (radius, μm) | 10.843 | Predicted based on in vitro Dissolution profile (SIVA) (S50) | ‐ | |
| Distribution type | Monodisperse | ‐ | ||
| Particle density (g/ml) | 1.2 | Simcyp default | ‐ | |
| Solubility (mg/L) | 30 | (S49) | 30 | (S49) |
| Dissolution shape | ‐ | 0.48 | Estimated (PE) | |
| Dissolution time (50% dissolved) | ‐ | 10 | (S50) | |
| Intestinal transport | ||||
| V(J)max,BCRP (pmol/min/pmol transporter) | 13302.9 | Estimated (PE) | 338.7 | Estimated (PE) |
| K m (μM) | 5 | Assumed based on other statins | 5 | Assumed based on other statins |
| Distribution | ||||
| Calculation Method | Poulin and Theil | Poulin and Theil | ||
| K p,scalar | 0.2 | Set to match predicted V ss (2 L/kg) from animal i.v. data | ‐ | |
| Cellular permeability (cm/min) | ‐ | 0.26 | Calculated from PK‐Sim Standard method | |
| Elimination | ||||
| Enzyme kinetics | ||||
| Vmax,CYP3A4 (pmol/min/mg prot) | 5895.6 | (24) | 5895.6 | (24) |
| K m,CYP3A4 (μM) | 30.7 | (24) | 30.7 (1.23) | (24) |
| f u,mic | 0.04 | Internally measured | (Applied as K m,u ) | Internally measured |
| Conversion to SVA | ||||
| Plasma | ||||
| Esterase (t 1/2)[min] | 368 | (19) | ‐ | |
| Vmax,PON1 (pmol/min/mg prot) | ‐ | 618.63 | Estimated (PE) | |
| K m,PON1 (μM) | ‐ | 103.1 | (18) | |
| Liver | ||||
| Vmax,CES1 (pmol/min/mg prot) | 500 | (18) | 500 | (18) |
| K m,CES1 (μM) | 87.4 | (18) | 87.4 (3.5) | (18) |
| f u,mic | 0.04 | Internally measured | (Applied as K m,u ) | Internally measured |
| SVA | ||||
|---|---|---|---|---|
| Simcyp | PK‐Sim | |||
| Parameter | Value | Reference | Value | Reference |
| Molecular weight (g/mol) | 436.6 | Drug bank | 436.6 | Drug bank |
| f u —experimental | 0.057 | (26) | 0.057 | (26) |
| B:P—experimental | 0.75 | Internal database | 0.75 | Internal database |
| LogPo:w | 4.235 | Drug bank | 2.21 | Estimated (PE) |
| Compound type | Acid | Drug bank | Acid | Drug bank |
| pKa | 4.31 | Drug bank | 4.31 | Drug bank |
| Solubility (mg/L) | 11 (pH = 7) | Predicted Phytia tool | ||
| Distribution | ||||
| Calculation method | Rodger | PK‐Sim Standard | ||
| K p,scalar | 2 | Set to match predicted Vss (0.25 L/kg) from animal i.v. data | ‐ | |
| Cellular permeability (cm/min) | ‐ | 6.79 E‐4 | Calculated from charge dependent Schmitt normalized to PK‐Sim | |
| Elimination | ||||
| Enzyme kinetics | ||||
| Non‐specific liver CLint (μl/min/mg. prot) | 55 | (25) | 1.22 | Estimated (PE) |
| Conversion to SVL | ||||
| Plasma | ||||
| Vmax,PON1 (pmol/min/mg prot) | ‐ | 618.63 | Co‐estimated with Vmax PON1 SVL | |
| K m,PON1 (μM) | ‐ | 103.1 | Li et al. 2019 | |
| Reference concentration | ‐ | 0.125 | Assumed based on in vitro data (19) | |
| Liver | ||||
| CLint,UGTA1 (μl/min/mg. prot) | ‐ | 0.4 | (21) | |
| Reference concentration (pmol/mg prot) | ‐ | 34.3 | (S58) | |
| Transporter | ||||
| CLPD (ml/min/mill.hep) | 0.005 | Estimated (PE) | ‐ | |
| Liver permeability | ‐ | 1.23 E‐6 | Calculated based on cellular permeability | |
| V(J)max,OATP1B1 (pmol/min/pmol transp) | 9.16 | Estimated (PE) | 2.82 | Estimated (PE) |
| K m,OATP1B1 (μM) | 2 | (31) | 2 | (31) |
Abbreviations: ADAM, advanced dissolution absorption metabolism model; B:P, blood‐to‐plasma ratio; CLint, intrinsic clearance; CLPD, tissue passive permeability; f u,mic, fraction unbound drug in microsomal incubation; f u , fraction unbound in plasma; K m,u , unbound Michaelis constant; K m , Michaelis constant; K p,scalar, tissue‐plasma partition coefficient scalar; LogPo:w, the octanol/water partition coefficient; PE, parameter estimation; P eff,man, effective intestinal permeability in man; prot, protein; SIVA, Simcyp In vitro data Analysis; SVA, simvastatin acid; SVL, simvastatin lactone; t 1/2, terminal half‐life; Vmax, maximum velocity of the metabolic reaction; V ss, volume of distribution at steady state.
Set by the type value of hematocrit and blood cell to plasma partition coefficient (see Appendix S2).