Table II.
Parameter Values of the Simple (Without Covariates) and Final (With Covariates) Population Pharmacokinetic Models and Results of the Bootstrap Analysis
| Parameter | Simple model of simultaneous analysis | Final model of simultaneous analysis | Bootstrap of final simultaneous model |
|---|---|---|---|
| Value (RSE) | Value (RSE) | Median (2.5–97.5 percentile) | |
| Fixed effects | |||
| Ka = Ktr | 0.199 (11%) | – | – |
| Ka = KtrMorbidly obese (min−1) | – | 0.117 (15%) | 0.114 (0.08–0.15) |
| Ka = KtrBariatric patients (min−1) | – | 0.267 (19%) | 0.263 (0.08–0.45) |
| F | 0.560 (10%) | 0.537 (9%) | 0.543 (0.44–0.63) |
| CL (L/min) | 0.381 (26%) | – | – |
| CLMorbidly obese (L/min) | – | 0.385 (11%) | 0.366 (0.29–0.48) |
| fCLBariatric patients(L/min) | – | 1.68 (7%) (* CL morbidly obese = 0.647) | 1.70 (1.18–2.18) (* CL morbidly obese = 0.634) |
| Q (L/min) | 0.888 (21%) | – | – |
| QMorbidly obese (L/min) | – | 0.669 (24%) | 0.764 (0.11–1.23) |
| fQBariatric patients (L/min) | – | 3.22 (32%) (* Q Morbidly obese = 2.15) | 2.907 (−22.6–29.0) (*Q Morbidly obese = 3.71) |
| Q2 | 0.644 (21%) | 0.551(23%) | 0.548 (0.25–0.86) |
| Vcentral (L) | 54.7 (17%) | – | – |
| Vcentral Morbidly obese = Vmedian BW *(1 + X*(BW-median BW)) | |||
| Vmedian BW | – | 37.3 (18%) | 37.2 (17.8–56.8) |
| X | – | 0.0435 (92%) | 0.052 (−0.42–0.51) |
| Vcentral Bariatric patients (L) | – | 37.3 (18%) | 37.2 () |
| V1st peripheral (L) | 247 (30%) | – | – |
| VPeripheral Morbidly obese = Vmedian BW*(BW/median BW)Y | |||
| Vmedian BW | – | 106 (17%) | 113 (20.9–190.3) |
| Y | – | 3.93 (20%) | 3.99 (1.9–5.9) |
| V1st peripheral Bariatric patients (L) | – | 106 (17%) | 113 (1.9–5.9) |
| fV2nd peripheral | 0.169 (25%) (*V 1st peripheral = 42 L) | 0.359 (27%) (*V 1st peripheral = 38 L) | 0.311 (0.13–0.58) (*V 1st peripheral = 40 L) |
| Interindividual variability (%) | |||
| Ktr = Ka | 50 (17%) | 42.4 (15%) | 40.6 (27–54) |
| CL | 41.5 (24%) | 19.7 (38%) | 17.7 (−14–32) |
| F | 28.6 (23%) | 33.4 (18%) | 32.6 (16–45) |
| Vcentral | 60.8 (20%) | 53.7 (39%) | 54.3 (−49–102) |
| V1st peripheral | 0 FIX | 0 FIX | 0 FIX |
| Proportional residual error (%) | |||
| 46.2 (6%) | 42.1 (5%) | 41.0 (12.2) | |
| OFV | 6218 | 5885 | 5997 (804) |
BW body weight (median = 127 kg for all data), CL Clearance (L/min), F Oral bioavailability, fCL Bariatric patients (L/min) fraction of midazolam clearance of morbidly obese patients to estimate bariatic patient clearance, fQ Bariatric patients fraction of intercompartmental clearance of morbidly obese patients to estimate intercompartmental clearance of bariatric patients, fV peripheral fraction of first peripheral volume of distribution to estimate second peripheral volume, Ktr transit compartment rate (min−1), Ka oral absorption rate (min−1), OFV Objective function value (-2LL), Q intercompartmental clearance (L/min), RSE(%) relative standard error, V Volume of distribution (L), V Peripheral first peripheral volume of distribution