Table 4.
Parameter estimates and covariate relations of the final pharmacokinetic–pharmacodynamic interaction model
| Parameterization | Unit | Population estimate | RSE (%) | Bootstrap (n = 1000) 95% CI |
|---|---|---|---|---|
| Pharmacokinetic model rocuronium | ||||
| CL = CLAGE×Θ× (BW/70)0.75 | l min−1 | 0.269 | 1.79 | 0.259–0.277 |
| CLAGE = 1 +Θ× (AGE – 43.0) | −0.00678 | 16.1 | −0.00887 to −0.00490 | |
| IIV CL (shrinkage 12%) | % | 32.4 | 11.1 | 29.0–35.6 |
| V1 = V1CR×Θ× (BW/70)1 | l | 4.73 | 2.68 | 4.46–4.98 |
| V1CR = Exp[Θ× (CR – 119)] | −0.00143 | 26.4 | −0.00214 to −0.00073 | |
| IIV V1 (shrinkage 28%) | % | 23.8 | 33.6 | 17.6–31.1 |
| Q2 = Q2RAC×Θ× (BW/70)0.75 | l min−1 | 0.279 | 5.27 | 0.253–0.309 |
| Non-Asian: Q2RAC = 1 | ||||
| Asian: Q2RAC = 1 +Θ | −0.212 | 38.2 | −0.340 to −0.060 | |
| V2 = V2AGE×Θ× (BW/70)1 | l | 6.76 | 2.22 | 6.48–7.12 |
| V2AGE = Exp[Θ× (AGE – 43.0)] | 0.00613 | 20.6 | 0.00373–0.00851 | |
| IIV V2 (shrinkage 37%) | % | 32.2 | 21.6 | 28.5–35.9 |
| Residual error (shrinkage 14%) | % | 20.0 | 10.8 | 17.9–22.1 |
| Pharmacokinetic model sugammadex | ||||
| CL = CLBW× (REN ×Θ) | l min−1 | 0.093 | 1.47 | 0.0902–0.0958 |
| REN = [2 × CR/(CR+119)]Θ | 1.29 | 4.77 | 1.19–1.39 | |
| CLBW = 1 +Θ× (BW – 74.5) | 0.00378 | 19.1 | 0.00152–0.00571 | |
| IIV CL (shrinkage 25%) | % | 22.4 | 18.1 | 18.2–25.7 |
| V1 = V1BW× V1RAC×Θ× (BW/70)1 | l | 4.42 | 2.35 | 4.21–4.64 |
| V1BW = 1 +Θ× (BW – 74.5) | −0.00354 | 23.1 | −0.00549 to −0.00178 | |
| Non-Asian: V1RAC = 1 | ||||
| Asian: V1RAC = 1 +Θ | −0.16 | 22.9 | −0.228 to −0.091 | |
| Q2 = Θ× (BW/70)0.75 | l min−1 | 0.206 | 4.69 | 0.188–0.225 |
| V2 = V2CR×Θ× (BW/70)1 | l | 6.35 | 2.82 | 6.00–6.71 |
| V2CR = Exp[Θ× (CR – 119)] | −0.00305 | 18.3 | −0.0041 to −0.0020 | |
| Residual error (shrinkage 3%) | % | 36.3 | 17.7 | 30.1–42.0 |
| Pharmacokinetic model complex | ||||
| kd | µm | 0.0559 | Fixed | |
| loge(k2) | min−1 | −3.38 | 16.5 | −4.20 to −1.43 |
| Pharmacodynamic model rocuronium | ||||
| keo = keoSEV×Θ× (BW/70)−0.25 | min−1 | 0.134 | 6.49 | 0.118–0.153 |
| No sevoflurane: keoSEV = 1 | ||||
| Sevoflurane: keoSEV = 1 +Θ | −0.567 | 8.94 | −0.668 to −0.467 | |
| IIV keo (shrinkage 0%) | % | 41.7 | 14.8 | 35.1–47.2 |
| EC50 = EC50SEV×Θ | µm | 1.62 | 3.68 | 1.50–1.75 |
| No sevoflurane: EC50SEV = 1 | ||||
| Sevoflurane: EC50SEV = 1 +Θ | −0.395 | 12.0 | −0.476 to −0.293 | |
| IIV EC50 (shrinkage 0%) | % | 24.9 | 16.9 | 19.9–28.4 |
| r (correlation keo and EC50) | 0.37 | 32.9 | 0.191–0.455 | |
| Hill = Θ | 7.52 | 5.84 | 6.99–8.15 | |
| IIV Hill (shrinkage 2%) | % | 41.1 | 22.0 | 32.7–48.5 |
| E0 = Θ× 100 | T4/T1 | 1.04 | 1.51 | 1.01–1.07 |
| IIV E0 (shrinkage 2%) | % | 11.1 | 21.5 | 8.5–13.3 |
| Residual error (shrinkage 5%) | T4/T1 | 2.70 | 7.03 | 2.50–2.87 |
| Pharmacodynamic model sugammadex | ||||
| ks = Exp(Θ) × (BW/70)−0.25 | min−1 µm−1 | −3.43 | 0.222 | −3.57 to −2.68 |
| IIV ks (shrinkage 3%) | % | 114% | 14.9 | 0.966–1.90 |
| Residual error (shrinkage 0%) | T4/T1 | 3.24 | 4.39 | 3.12–3.45 |
Pharmacokinetic and PK–PD parameters are as presented in Figure 1. RSE(%), relative standard error describing uncertainty in the parameter (100 × SE/population estimate). SE, asymptotic standard error estimate of the parameter (taken from $COV of NONMEM). IIV, interindividual variability. CI, confidence interval. Parameterization complex formation kd = k2/k1. SEV, sevoflurane. RAC, race. BW, bodyweight, CR, creatinine clearance. Emax for rocuronium NMB is set equal to E0.