TABLE 3.
Population pharmacokinetic parameter estimates from a nonlinear mixed-effect model for midazolam, diclofenac, dextromethorphan, and chlorzoxazone
Data are estimates (S.E. %).
| Parameters | Midazolam CL = θ1 + CAG × θ5 V1 = θ2 + TEMG × θ6 | Diclofenac CL = θ1 + TEMG × θ5 | Dextromethorphan V1 = θ2 + TEMG × θ5 | Chlorzoxazone CL = θ1 + CAG × θ5 V2 = θ4 + TEMG × θ6 |
|---|---|---|---|---|
| CL (θ1) (l · h−1 · kg−1) | 0.990 (12.7) | 0.587 (6.55) | 0.504 (5.33) | 0.433 (5.64) |
| V1 (θ2) (l/kg) | 0.258 (2.42) | 0.138 (2.31) | 0.204 (2.63) | 0.142 (1.68) |
| Q (θ3) (l · h−1 · kg−1) | 0.644 (10.6) | 0.507 (8.22) | 1.01 (12.5) | 0.889 (10.6) |
| V2 (θ4) (l/kg) | 1.0 (11.9) | 0.854 (15.1) | 1.42 (15.5) | 0.970 (15.1) |
| Covariate θ5 | −0.318 (11.5) | −0.184 (9.06) | −0.0685 (3.2) | −0.204 (6) |
| Covariate θ6 | −0.0786 (16.4) | −0.478 (15.8) | ||
| w2 (CL) | 0.119 (6.21) | 0.149 (5.48) | 0.269 (11.3) | 0.126 (3.54) |
| ω2 (V1) | 0.018 (14.6) | 0.082 (12.4) | 0.0385 (2.86) | |
| ω2 (Q) | 0.460 (12.4) | 0.312 (12.6) | 0.234 (8.99) | 0.218 (9.44) |
| ω2 (V2) | 0.214 (14.7) | 0.406 (11.8) | 0.170 (5.73) | 0.170 (5.91) |
| σ2 | 0.107 (12.5) | 0.119 (1.87) | 0.0838 (1.47) | 0.0662 (0.877) |
| Final OFV | 1268.8 | 1939.5 | 1880.9 | 2094.5 |
| OFV change | 10.4 | 6.0 | 4.7 | 23.6 |
| p value | <0.05 | <0.05 | <0.05 | <0.01 |
CL, clearance; V1, central compartment of distribution; Q, intercompartment clearance; V2, peripheral compartment of distribution; CAG, CA categorical covariate (0 = sham, 1 = CA); TEMG, temperature categorical covariate (0 = normothermia, 1 = hypothermia); ω2, interindividual variability; σ2, residual error; OFV, objective function value; covariate θ5, effect of the first significant covariate on the specific PK parameters (CA for midazolam and chlorzoxazone and temperature for dextromethorphan and diclofenac); covariate θ6, effect of the second significant covariate found on specific PK parameters (temperature for midazolam and chlorzoxazone).