Table 2.
Population pharmacokinetic parameters of the final model for midazolam and results of the bootstrap analysis (250/250 resamples successful)
| Parameter | Model estimates (RSE%) | Bootstrap estimates (95% confidence interval) |
|---|---|---|
| CL= CLmesor+Amp x cos((2π/1440)*(Time-Acrophase)) | ||
| CLmesor (L/min) | 0.379 (4.8) | 0.380 (0.344–0.417) |
| Amp (L/min) | 0.027 (14.8) | 0.028 (0.017–0.039) |
| Acrophase (min) | 1,130 (2.9) | 1,130.2 (1,005.3–1,204.7) |
| Vcentral (L) | 18.2 (5.4) | 18.4 (15.3–20.9) |
| Vperipheral1 = Vperipheral2 (L) | 22.5 (2.5) | 22.4 (20.2–26.2) |
| Q (L/min) | 0.27 (6.8) | 0.269 (0.209–0.334) |
| Q2 (L/min) | 1.31 (8.5) | 1.29 (1.08–1.56) |
| Ka = Ktr (min−1) | 0.053 (5.8) | 0.053 (0.048–0.061) |
| Fraction Ka at 14:00 | 1.41 (4.7) | 1.41 (1.07–1.78) |
| F= Fmesor+Amp x cos((2π/1440)*(Time-Acrophase)) | ||
| F | 0.277 (7.1) | 0.275 (0.244–0.313) |
| Amp | 0.041 (17.3) | 0.041 (0.026–0.055) |
| Acrophase (min) | 734 (5.3) | 739.7 (667.0–821.0) |
| Interindividual variability | ||
| CL (%) | 16.2 (21) | 15.2 (9.7–19.6) |
| Ka (%) | 19.1 (21.9) | 18.7 (10.7–24.2) |
| F (%) | 23.3 (22.2) | 22.7 (15.8–28.8) |
| Interoccasion variability | ||
| F (%) | 14.8 (10.5) | 14.5 (11.5–17.9) |
| Residual proportional error | ||
| σ oral (%) | 18.0 (5.6) | 17.8 (15.8–19.8) |
| σ intravenous(%) | 15.4 (6.1) | 15.1 (13.2–17.3) |
| OFV (−2LL) | 2,299 | 2,242 (1,723–2,730) |
Acrophase, peak time of the cosine function in minutes after midnight; Amp, amplitude; CL, systemic clearance of midazolam; F, oral bioavailability; Ka, oral absorption rate constant; Ktr, transit compartment rate constant; OFV, objective function value; Q, intercompartmental clearance of midazolam between central and first peripheral compartment; Q2, intercompartmental clearance of midazolam between central and second peripheral compartment; RSE, relative standard error (%); V, volume of distribution.