Table 1.
Pharmacokinetic and pharmacodynamic parameters of the nine virtual compounds
| Compound | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
|---|---|---|---|---|---|---|---|---|---|---|
| Summary of PK–PD characteristics | ||||||||||
| Compartmentsa | 1 | 2 | 2 | 2 | 2 | 2 | 2 | 3 | 3 | |
| Saturable eliminationb | – | – | – | – | – | + | – | – | – | |
| Auto-induction | – | – | – | – | – | – | + | – | + | |
| IIV PK | Moderate | Moderate | Large | Moderate | Moderate | Moderate | Moderate | Moderate | Large | |
| IIV PD | Moderate | Moderate | Moderate | Large | Moderate | Moderate | Moderate | Moderate | Large | |
| Residual error PK | Moderate | Moderate | Moderate | Moderate | Large | Moderate | Moderate | Moderate | Moderate | |
| PK parameters | ||||||||||
| V 1 c | (L) | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| V max c | (mg/h) | 100 | 100 | 100 | 100 | 100 | 10 | 100 | 100 | 100 |
| K m | (mg/L) | 100 | 100 | 100 | 100 | 100 | 1 | 100 | 100 | 100 |
| V 2 c | (L) | 1 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| Q 2 | (L/h) | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
| V 3 c | (L) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 | 10 |
| Q 3 | (L/h) | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| I max | (%) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| ECI50 | (mg/L) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| MTTenz | (h) | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
| IIV V 1; V 2; V 3 d | (%) | 40 | 40 | 80 | 40 | 40 | 40 | 40 | 40 | 80 |
| IIV V max d | (%) | 30 | 30 | 60 | 30 | 30 | 30 | 30 | 30 | 60 |
| IIV Q 2; Q 3 d | (%) | 30 | 30 | 60 | 30 | 30 | 30 | 30 | 30 | 60 |
| IIV MTTenz d | (%) | 25 | 25 | 50 | 25 | 25 | 25 | 25 | 25 | 50 |
| Residual error PKe | (%) | 20 | 20 | 20 | 20 | 40 | 20 | 20 | 20 | 20 |
| PD parameters | ||||||||||
| Slope | (mg/L) | 0.25 | 0.25 | 0.25 | 0.25 | 0.25 | 0.25 | 0.25 | 0.25 | 0.25 |
| MTT | (h) | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 | 120 |
| Base | (109/L) | 5.3 | 5.3 | 5.3 | 5.3 | 5.3 | 5.3 | 5.3 | 5.3 | 5.3 |
| Gamma | 0.17 | 0.17 | 0.17 | 0.17 | 0.17 | 0.17 | 0.17 | 0.17 | 0.17 | |
| IIV sloped | (%) | 45 | 45 | 45 | 90 | 45 | 45 | 45 | 45 | 90 |
| IIV MTTd | (%) | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 |
| IIV based | (%) | 35 | 35 | 35 | 35 | 35 | 35 | 35 | 35 | 35 |
| Residual error PDe | (%) | 45 | 45 | 45 | 45 | 45 | 45 | 45 | 45 | 45 |
aAll data were simulated from three compartment models, but the contribution of one or both peripheral compartments was small for compounds 1–7
bAll data were simulated from a model with Michaelis Menten elimination, but saturation was only evident if K m was relatively low (1 mg/L)
cAllometric scaling was applied to V max ((WT/70)0.75) and to the volumes of distribution V 1, V 2, V 3 ((WT/70)1)
dIIV = inter-individual variability; geometric standard deviations are listed
eResidual errors were additive on a logarithmic scale; geometric standard deviations are listed