Table II.
Parameter Estimates of the Final Physiological Population PK Model
| Parameter definition | Parameter (unit) | Value (RSE%) [shrinkage %] | Bootstrap median | Bootstrap 90% CI | 70-kg individual |
|---|---|---|---|---|---|
| Midazolam | |||||
| Intrinsic hepatic clearance CLH,int,i = CLH,int,16kg × (WT/16)k1 | CLH,int,16kg (L/h) | 527.0 (7%) | 601.4 | 523.5–748.6 | 1057 |
| Exponent | k1 | 0.472 (16%) | 0.425 | 0.206–0.554 | 0.472 |
| Intrinsic gut wall clearance CLG,int,i = CLG,int,16kg × (WT/16)k2 | CLG,int,16kg (L/h) | 5.08 (10%) | 4.93 | 3.32–6.17 | 16.7 |
| Exponent | k2 | 0.807 (10%) | 0.881 | 0.622–1.27 | 0.807 |
| Volume of distribution (central) Vc,i = Vc,76kg × (WT/76)k3 | Vc,76kg (L) | 20.4 fix | – | – | 18.8 |
| Volume of distribution (two peripheral compartments) Vp,i = Vp,76kg × (WT/76)k3 | Vp1,76kg (L) V p2,76kg (L) |
55.2 fix 79.1 fix |
- - |
– | 50.8 72.9 |
| Exponent | k3 | 1 fix | – | – | 1 |
| Inter compartmental clearance Qcp1,i = Vcp1,16kg × (WT/16)k4 | Qcp1 (L/h) | 14.9 (19%) | 14.9 | 8.9–25.9 | 57.9 |
| Exponent | k4 | 0.92 (21%) | 1.03 | 0.796–1.65 | 0.92 |
| Inter compartmental clearance (2nd peripheral compartment) | Qcp2 (L/h) | 7.5 (10%) | 7.7 | 6.3–11.2 | 7.5 |
| 1-OH-midazolam (M) | |||||
| Fraction midazolam metabolized into 1-OH-midazolam | fM | 1 fix | – | – | 1 |
| Intrinsic hepatic clearance CLH,int,M,i = CLH,int,M,16kg × (WT/16)k5 | CLH,int,M,16kg (L/h) | 235.0 (6%) | 236.2 | 219.6–269.6 | 614.2 |
| Exponent | k5 | 0.651 (9%) | 0.615 | 0.451–0.750 | 0.651 |
| Intrinsic gut wall clearance CLG,int,M,i = k6 × CLG,int,i |
k6 | 18.4 (12%) | 19.2 | 10.6–198.2 | 18.4 |
| Volume of distribution VM,i = VM,76kg × (WT/76)k7 |
VM,76kg (L) | 65.7 fix | – | – | 60.5 |
| Exponent | k7 | 1 fix | – | – | 1 |
| Inter individual variability (variance) | |||||
| Intrinsic hepatic clearance | ω2 CLH,int | 0.25 (13%)[25%] | 0.24 | 0.16–0.32 | – |
| Intrinsic gut wall clearance | ω2 CLG,int | 1.20 (13%)[13%] | 1.25 | 1.04–1.56 | – |
| Inter compartmental clearance | ω2 Qcp1 | 1.05 (35%)[42%] | 1.05 | 0.26–1.85 | – |
| ω2 Qcp2 | 1.06 (31%)[46%] | 1.06 | 0.68–1.79 | – | |
| Intrinsic hepatic clearance 1-OH-midazolam (M) | ω2 CLH,int,M | 0.13 (18%)[31%] | 0.13 | 0.08–0.19 | – |
| Residual variability (variance) | |||||
| Proportional error (Midazolam) | 0.166 (8%)[19%] | 0.169 | 0.150–0.199 | – | |
| Additive error (Midazolam), nmol/L | 0.001 fix | – | – | – | |
| Proportional error (1-OH-midazolam) | 0.292 (11%)[9%] | 0.271 | 0.225–0.309 | – | |
| Additive error (1-OH-midazolam), nmol/L | 0.528 (10%)[9%] | 0.454 | 0.130–0.826 | – | |
RSE: relative standard error. CI: the 5th–95th percentiles are shown, indicating a 90% confidence interval. Bootstrap n = 250. Inter-individual and residual variability values are shown as variance estimates. Intrinsic clearance values are reported for the whole organ