Table 2.
Population pharmacokinetic parameters of the simple and final pharmacokinetic model for midazolam in 20 morbidly obese patients and 12 healthy volunteers and results from a bootstrap analysis of the final model (479/500 re-samples successful)
| Parameter | Simple model (RSE%) | Final model (RSE%) | Bootstrap (SE) |
|---|---|---|---|
| Fixed effects | |||
| CL (L/min) | 0.36 (4.9) | 0.359 (4.4) | 0.358 (0.016) |
| F | 0.414 (12.8) | – | |
| F morbidly obese | – | 0.603 (13.2) | 0.603 (0.081) |
| F healthy volunteers | – | 0.284 (7.0) | 0.286 (0.020) |
| Ka (min−1) = Ktr | 0.086 (3.4)a | – | |
| Ka = Ktr morbidly obese | – | 0.057 (13.6)b | 0.058 (0.059) |
| Ka = Ktr healthy volunteers | – | 0.13 (5.1)b | 0.130 (0.006) |
| Vcentral (L) | 36.4 (7.8) | – | |
| Vcentral = V127 kg × (1 + Z × (TBW – 127)) | |||
| Vcentral, 127 kg | – | 44.1 (16.1) | 43.6 (6.9) |
| Z | – | 0.0105 (15.8) | 0.0102 (0.002) |
| Vmidazolam peripheral (L) | 76.6 (8.4) | – | |
| Vperipheral = V127 kg × (TBW/127)W | |||
| Vperipheral, 127 kg | – | 139 (15.2) | 138.7 (22.9) |
| W | – | 3.06 (8.2) | 3.07 (0.28) |
| Q (L/min) | 1.31 (12.8) | 1.33 (11.8) | 1.33 (0.143) |
| Q2 (L/min) | 0.153 (12.1) | 0.15 (14.6) | 0.15 (0.023) |
| Interindividual variability (%) | |||
| CL | 19.7 (32.6) | 18.1 (30.7) | 17.2 (14.6) |
| F | 61.2 (20.8) | 26.4 (17.4) | 25.4 (14.6) |
| Ka = Ktr | 50.7(10.9) | 41.4 (12.8) | 39.9 (18.4) |
| Vcentral | 102.8 (13.2) | 55.2 (17.5) | 53.5 (30.8) |
| Vperipheral | 152.3 (13.9) | 34.4 (26.5) | 33.6 (23.7) |
| Correlation between eta Vcentral and Vperipheral | 0.783 (50.0) | 0.12 (24.5) | 0.10 (0.058) |
| Residual variability (%) | |||
| Proportional error healthy volunteers | 10.0 (21.5) | 10.0 (21.3) | 9.9 (4.4) |
| Proportional error morbidly obese patients | 31.0 (17.1) | 46.7 (11.6) | 46.6 (15.6) |
| Additive error morbidly obese patients | 3.1 (37.3) | ||
| OFV | 4,077 | 4,003 | 3,982 (145) |
CL systemic clearance of midazolam, F oral bioavailability, Ka oral absorption rate, Ktr transit compartment rate, Q inter-compartmental clearance of midazolam between the central and first peripheral compartment, Q2 inter-compartmental clearance of midazolam between the central and second peripheral compartment, OFV objective function value, RSE relative standard error, SE standard error, TBW total body weight, V volume of distribution
aMean transit time is 46.5 min
bMean transit times are 70.2 and 30.8 min, respectively