Table 2.
Summary of input parameters used for repaglinide simulations
| Simcyp default | CYP3A4–CYP2C8 correlation | Comments | |
|---|---|---|---|
| Molecular weight (g mol −1 ) | 452.6 | 452.6 | |
| log P | 3.98 | 3.98 | |
| Compound type | Ampholyte | Ampholyte | |
| pK a | 4.2, 6.0 | 4.2, 6.0 | |
| Blood/plasma ratio | 0.62 | 0.62 | |
| Fraction unbound in plasma | 0.023 | 0.023 | |
| Absorption | |||
| Model | First‐order | First‐order | |
| Fraction absorbed | 0.98 | 0.98 | |
| Absorption rate constant (l h −1 ) | 1.6 | 1.6 | |
| Fraction of drug unbound in enterocyte | 1 | 1 | |
| Caco‐2 permeability (×10 −6 cm s −1 ) | 24.1 | 24.1 | |
| Predicted P eff,man (×10 −4 cm s −1 ) | 3.89 | 3.89 | |
| Distribution | |||
| Model | Full PBPK | Full PBPK | |
| V ss (l kg −1 ) | 0.24 | 0.24 | |
| K p scalar | 3.3 | 3.3 | |
| Elimination | |||
| HLM, CYP2C8 K m (μM) | 2.3 | Transferred to parameter for recombinant | |
| HLM, CYP2C8 V max (pmol min −1 mg −1 ) | 300.8 | Transferred to parameter for recombinant | |
| HLM, CYP3A4 K m (μM) | 13.2 | Transferred to parameter for recombinant | |
| HLM, CYP3A4 V max (pmol min −1 mg −1 ) | 958.2 | Transferred to parameter for recombinant | |
| Recombinant, CYP3A4 K m (μM) | 13.2 | CYP3A4 Km in HLM | |
| Recombinant, CYP3A4 V max (pmol min −1 mg −1 ) | 6.99 | Calculated from CYP3A4 Vmax in HLM | |
| Recombinant, CYP3A5 K m (μM) | 2.3 | CYP2C8 Km in HLM | |
| Recombinant, CYP3A5 V max (pmol min −1 mg −1 ) | 12.53 | Calculated from CYP2C8 Vmax in HLM | |
| CL R (l h −1 ) | 0.013 | 0.013 | |
| Hepatic transport | |||
| OATP1B1 CL int,T (μL min −1 million cells −1 ) | 246 | 246 | |
| CL PD (ml min −1 million hepatocytes −1 ) | 0.089 | 0.089 | |
CLint, T, transporter‐mediated intrinsic clearance; CLPD, passive diffusion clearance; CLR, renal clearance; Full PBPK model, full physiologically‐based pharmacokinetic model; HLM, human liver microsomes; Km, Michaelis–Menten constant; Kp, tissue to plasma partition coefficient; Peff,man, human jejunum permeability; Vmax, maximum rate of metabolism; Vss, volume of distribution at steady state