Table 3.
Population parameter values for the final adopted composite midazolam model and the model with interaction
| Model parameters | Parameter name | Final model (N = 99 (4568 obs)) |
Interaction (N = 99 (6606 obs)) |
Parameter uncertainty: | |||
|---|---|---|---|---|---|---|---|
| Value | RSE [%] | Shrinkage [%] | Value | RSE [%] | 95% CIa [lower, upper] |
||
| Structural & covariate parameters | |||||||
| Vc [L] | MDZ central volume | 19.5 | 8.08 | FIXED | 17.7, 21.4 | ||
| Vp1 [L] | MDZ peripheral 1 volume | 41.0 | 7.92 | FIXED | 37.0, 45.8 | ||
| Vp2 [L] | MDZ peripheral 2 volume | 23.8 | 4.75 | FIXED | 22.6, 25.1 | ||
| Qp1 [h−1] | MDZ inter-compartment clearance 1 | 8.00 | 9.90 | FIXED | 7.10, 9.18 | ||
| Qp2 [h−1] | MDZ inter-compartment clearance 2 | 46.1 | 8.26 | FIXED | 41.6, 51.8 | ||
| ka parent [h−1] | Absorption rate constant | 2.31 | 4.44 | FIXED | 2.20, 2.42 | ||
| F | Combined bioavailability | 0.276 | 3.35 | FIXED | 0.261, 0.291 | ||
| kmet [h−1] | Pre-systemic metabolism rate | 5.31 | 6.92 | FIXED | 4.83, 5.87 | ||
| Qmet [L· h−1] | MDZ clearance via metabolism | 24.1 | 2.00 | FIXED | 23.3, 25.1 | ||
| Vmet [L] | Metabolic central volume | 175.6 | 9.69 | FIXED | 162, 193 | ||
| VMP [L] | Metabolic peripheral 1 volume | 684.9 | 15.1 | FIXED | 604, 796 | ||
| VMP2 [L] | Metabolic peripheral 2 volume | 67.1 | 9.99 | FIXED | 56.4, 77.8 | ||
| QMP [h−1] | Metabolic inter-compartment clearance 1 | 59.6 | 9.18 | FIXED | 51.9, 67.7 | ||
| QMP,WT [h−1/70 kg] | Power of weight on QMP | 0.986 | 31.0 | FIXED | 0.409, 1.53 | ||
| QMP2 [h−1] | Metabolic inter-compartment clearance 2 | 127.4 | 11.0 | FIXED | 101, 155 | ||
| CLmet [L· h−1] | Metabolic clearance | 196.8 | 4.57 | FIXED | 186, 208 | ||
| EarlyMDZ,prop | Early proportional error for MDZ (split: 0.5 h) | 0.503 | 3.51 | FIXED | 0.471, 0.534 | ||
| LateMDZ,prop | Late proportional error for MDZ (split: 0.5 h) | 0.149 | 4.16 | FIXED | 0.143, 0.154 | ||
| Early1′-OHMDZ,prop | Early proportional error for 1′-OH MDZ (split: 0.5 h) | 0.556 | 3.32 | FIXED | 0.522, 0.590 | ||
| Late1′-OHMDZ,prop | Late proportional error for 1′-OH MDZ (split: 0.5 h) | − 0.215 | 3.95 | FIXED | − 0.224, − 0.208 | ||
| Inter-individual variability | |||||||
| ω2Vc | Variance of MDZ central volume | 0.378 | 10.3 | 15.0 | FIXED | 0.311, 0.443 | |
| ω2Vp1 | Variance of MDZ peripheral 1 volume | 0.410 | 12.0 | 26.0 | FIXED | 0.339, 0.491 | |
| ω2Qp1 | Variance of MDZ inter-compartment clearance 1 | 0.502 | 12.4 | 9.1 | FIXED | 0.426, 0.590 | |
| ω2F | Variance or bioavailability | 0.234 | 13.4 | 19.4 | FIXED | 0.182, 0.289 | |
| ω2kmet | Variance of pre-systemic metabolism rate | 0.369 | 9.76 | 12.9 | FIXED | 0.310, 0.445 | |
| ω2Qmet | Variance of MDZ clearance via metabolism | 0.0934 | 39.3 | 48.6 | FIXED | 0.0339, 0.142 | |
| ω2Vmet | Variance of metabolic central volume | 0.398 | 9.97 | 13.9 | FIXED | 0.326, 0.464 | |
| ω2QMP | Variance of metabolic inter-compartment clearance 1 | 0.485 | 12.2 | 20.9 | FIXED | 0.401, 0.585 | |
| ω2CLmet | Variance of metabolic clearance | 0.133 | 31.7 | 56.1 | FIXED | 0.0602, 0.196 | |
| ω2Vmet ~ ω2Vc | Covariance of MDZ and 1′-OH MDZ central volumes | 0.731 | 13.2 | – | FIXED | 0.264, 0.392 | |
| Inter-occasion variability | |||||||
| ω2F | Inter-occasion variability for bioavailability | 0.162 | 14.0 | 40.3 | FIXED | 0.125, 0.202 | |
| ω2Qmet | Inter-occasion variability for MDZ clearance via metabolism | 0.152 | 15.5 | 17.3 | FIXED | 0.127, 0.182 | |
| ω2CLmet | Inter-occasion variability for metabolic clearance | 0.293 | 19.3 | 3.2 | FIXED | 0.251, 0.353 | |
| Treatment effect | |||||||
| kmet,IND [h−1] | Induction effect on kmet | – | – | 12.4 | 30.6 | 9.20, 16.7 | |
| FIND [%] | Induction effect on bioavailability | – | – | − 20.0 | 5.59 | − 21.2, − 18.6 | |
| Qmet,IND [h−1] | Induction effect on midazolam clearance | – | – | 38.0 | 20.5 | 30.5, 46.3 | |
| Vc,INH2 [L] | Effect of irreversible inhibition on central volume | – | – | 51.8 | 15.7 | 40.8, 65.2 | |
| kmet,INH2 [h−1] | Irreversible inhibition effect on kmet | – | – | − 5.24 | 0.362 | − 5.26, − 5.20 | |
| FINH1 [%] | Reversible inhibition effect on bioavailability | – | – | 37.9 | 6.87 | 33.4, 43.2 | |
| FINH2 [%] | Irreversible inhibition effect on bioavailability | – | – | 134 | 14.2 | 114, 159 | |
| Qmet,INH1 [h−1] | Reversible inhibition effect on midazolam clearance | – | – | − 16.3 | 3.77 | − 16.9, − 15.7 | |
| Qmet,INH2 [h−1] | Irreversible inhibition effect on midazolam clearance | – | – | − 12.7 | 9.99 | − 14.0, − 11.2 | |
| CLmet,INH1 [L· h−1] | Reversible inhibition effect on metabolic clearance | – | – | − 64.1 | 20.7 | − 77.2, − 49.8 | |
| CLmet,INH2 [L· h−1] | Irreversible inhibition effect on metabolic clearance | – | – | 1117 | 11.2 | 901, 1387 | |
| Earlyprop,INH | Early proportional error for inhibition | – | – | 0.483 | 4.49 | 0.456, 0.512 | |
| Lateprop,INH | Later proportional error for inhibition | – | – | − 0.267 | 6.01 | − 0.281, − 0.256 | |
Relative standard errors for inter-individual variability are given on the approximate standard deviation scale (standard error/variance estimate)/2; CI confidence interval, MDZ midazolam, obs observations, prop. Proportional, RSE relative standard error
aCalculated using sampling importance resampling (SIR)