Table 2.
Parameter estimates of the base model, final model and bootstrap analysis
| Parameter | Structural model | Final model | RSE (%) | Shrinkage (%) | Bootstrap of the final model | ||
|---|---|---|---|---|---|---|---|
| Estimate | 95 % CI (lower) | 95 % CI (upper) | |||||
| OFV | −323.7 | −351.6 | |||||
| Morphine | |||||||
| F | 0.28 | 0.30 | 13.6 | – | 0.31 | 0.18 | 0.53 |
| CL (L/h) | 37.2 | 47.5 | 11 | – | 49.9 | 39.1 | 75.6 |
| V1 (L) | 185 | 190 | 28 | – | 190 | 116 | 369 |
| Q (L/h) | 75 | 76.1 | 35.7 | – | 65.1 | 9.95 | 146 |
| V2 (L) | 246 | 243 | 19 | – | 248 | 121 | 377 |
| M3G | |||||||
| F m1 | 0.55a | 0.55a | NA | – | 0.55a | 0.55a | 0.55a |
| CL (L/h) | 1.48 | 1.44 | 4.8 | – | 1.44 | 1.30 | 1.59 |
| V1 (L) | 7.65 | 8.02 | 33.2 | – | 7.75 | 3.62 | 14.9 |
| M6G | |||||||
| F m2 | 0.1a | 0.1a | NA | – | 0.1a | 0.1a | 0.1a |
| CL (L/h) | 1.87 | 1.78 | 6.8 | – | 1.79 | 1.56 | 2.05 |
| V1 (L) | 7.1 | 8.24 | 30.7 | – | 7.97 | 3.77 | 14.0 |
| Covariate effect on M3G and M6G clearance | |||||||
| eGFRb | 0.83 | 0.673 | 16.8 | – | 0.67 | 0.50 | 1.03 |
| Albumin | – | 1.1 | 23.3 | – | 1.06 | 0.332 | 1.56 |
| Covariate effect on M3G and M6G clearance | |||||||
| TTDc (Δ), days | – | 17.6 | 24.7 | – | 19.2 | 9.48 | 46.6 |
| TTDc (rate), days | – | 0.13 | 32 | – | 0.12 | 0.05 | 0.31 |
| Between-subject variability (%) | |||||||
| F | 48.2 | 37.8 | 38.3 | 9.5 | 38.7 | 1.7 | 58.0 |
| Morphine CL | 54.0 | 53.4 | 30.1 | 13.3 | 50.0 | 31.7 | 71.8 |
| M3G CL | 39.7 | 29.3 | 29.2 | 5.5 | 29.3 | 20.4 | 41.7 |
| M6G CL | 43.5 | 34.3 | 29.2 | 5.5 | 34.1 | 23.8 | 48.4 |
| M3G V1 | 135.5 | 151.7 | 31.4 | 6.1 | 147.9 | 80.3 | 203.1 |
| M6G V1 | 130.4 | 143.0 | 31.4 | 6.1 | 141.5 | 76.8 | 194.4 |
| Residual variability | |||||||
| Morphine | 0.448 | 0.432 | 10.4 | 10 | 0.425 | 0.335 | 0.510 |
| M3G | 0.250 | 0.246 | 9.3 | 10 | 0.239 | 0.194 | 0.282 |
| M6G | 0.261 | 0.265 | 6.6 | 10 | 0.254 | 0.218 | 0.294 |
RSE relative standard error, CI confidence interval, OFV objective function value, F bioavailability of oral morphine, CL clearance, V1 central compartment for morphine, V2 peripheral compartment for morphine, Q intercompartmental clearance of morphine, M3G morphine-3-glucuronide, M6G morphine-6-glucuronide, NA not applicable, F m1 fraction of morphine clearance responsible for M3G formation, F m2 fraction of morphine clearance responsible for M6G formation, eGFR estimated glomerular filtration rate, TTD time to death, MDRD Modification of Diet in Renal Disease, GFR glomerular filtration rate
aTransformation ratios for M3G and M6G were fixed to known literature values
bGFR was estimated using the standard four-variable MDRD equation
cTTD was incorporated as a first-order process, with TTDΔ (overall change in clearance) as the change in parameter value from its initial value and TTDrate (change in clearance per day as described by the first order process) as the first-order rate constant