Table 2.
Parameter estimates of the base model, final model, and bootstrap analysis
| Parameter | Structural model (shrinkage) | Final model (shrinkage) | Bootstrap estimate (95% CI) |
|---|---|---|---|
| Tlaga (h) | 0.38 | 0.38 | 0.38 |
| kaa (h–1) | 3.58 | 3.58 | 3.58 |
| CL/Fa (l h–1) | 23.0 | 23.0 | 23.0 |
| V1/Fa (l) | 692 | 692 | 692 |
| Q1/Fa (l h–1) | 11.6 | 11.6 | 11.6 |
| V2/Fa (l) | 5340 | 5340 | 5340 |
| KWB-IC a | 0.9 | 0.9 | 0.9 |
| RWB:IC | 12900 | 14100 | 14023 (12595–15633) |
| Covariate effect on CLa | |||
| CYP3A5*1 | 1.63 | 1.63 | 1.63 |
| CYP3A4*22 | 0.80 | 0.80 | 0.80 |
| Haematocrit (l l–1) | − 0.76 | − 0.76 | − 0.76 |
| Creatinine (μmol l–1) | − 0.14 | − 0.14 | − 0.14 |
| Albumin (g l–1) | 0.43 | 0.43 | 0.43 |
| Age (years) | − 0.43 | − 0.43 | − 0.43 |
| BSA (m2) | 0.88 | 0.88 | 0.88 |
| Covariate effect on V1a | |||
| Lean body weight | 1.52 | 1.52 | 1.52 |
| Covariate effect on RWB:IC | |||
| Lean body weight | – | 1.01 | 1.002 (0.56–1.54) |
| Haematocrit | – | − 1.22 | − 1.21 (− 1.96 to − 0.42) |
| IIV (%) | |||
| CLa | 38.6 | 38.6 | 38.6 |
| V1a | 49.2 | 49.2 | 49.2 |
| V2a | 53.0 | 53.0 | 53.0 |
| Qa | 78.7 | 78.7 | 78.7 |
| RWB-IC | 42.8 [31] | 38.9 [33] | 37.3 (21.7–52.5) |
| IOV (%) | |||
| CL/Fa | 13.6 | 13.6 | – |
| Residual variability | |||
| Proportional WB | 0.611 | 0.611 | 0.584 (0.292–0.874) |
| Proportional IC | 0.202 | 0.184 | 0.179 (0.139–0.210) |
| Additive IC | 37 | 36.8 | 36.1 (20.5–46.4) |
aFixed parameter. Whole-blood model parameter values were fixed at individual values using the previously reported model of Andrews et al. [23]; therefore, RSE, shrinkage, and bootstrap estimates are not reported.
CL clearance, CYP cytochrome P450, F bioavailability of oral tacrolimus, IIV inter-individual variability, IOV inter-occasion variability, Ka absorption rate constant, KWB-IC distribution rate constant, Q inter-compartmental clearance, RWB:IC ratio between whole-blood and intracellular tacrolimus, Tlag lag time, V1 central compartment, V2 peripheral compartment