Table 2.
Parameter estimates and bootstrap results for the theory-based population model
| Parameter | Final model estimate* | Mean bootstrap estimate | RSE % | Bootstrap 95% CI† |
|---|---|---|---|---|
| CLwb/F (l h−1) (HCT 45%, FFM 60 kg) | 16.1 | 15.7 | 10% | 12.6, 18.0 |
| V1wb/F (l) (HCT 45%, FFM 60 kg) | 125 | 122 | 11% | 95.8, 145 |
| Qwb/F (l h−1) (HCT 45%, FFM 60 kg) | 23.8 | 23.2 | 13% | 17.4, 28.9 |
| V2wb/F (l) (HCT 45%, FFM 60 kg) | 636 | 623 | 16% | 453, 834 |
| ka (h−1) | 1.01 | 1.03 | 9% | 0.87, 1.22 |
| tlag (h) | 0.41 | 0.41 | 3% | 0.39, 0.44 |
| Covariates effects on clearance | ||||
| CYP3A5 expresser‡ (factor) | 1.30 | 1.29 | 7% | 1.13, 1.46 |
| Covariates effects on bioavailability (F) | ||||
| CYP3A5 expresser‡ (factor) | 0.82 | 0.83 | 8% | 0.71, 0.98 |
| Time, early | ||||
| Fday 2 (factor) | 2.68 | 2.69 | 8% | 2.28, 3.09 |
| Prednisolone dose | ||||
| Predmax (%) | −67 | −66 | 19% | −41, −89 |
| Pred50 (mg) | 35 | 33 | 40% | 7, 50 |
| Between subject variability | ||||
| CLwb/F (CV %) | 40 | 40 | 7% | 35, 46 |
| V1wb/F (CV %) | 54 | 53 | 11% | 42, 64 |
| Qwb/F (CV %) | 63 | 64 | 13% | 46, 81 |
| Fday2 (CV %) | 57 | 57 | 14% | 42, 71 |
| Correlations | ||||
| CLwb/F ∼ V1wb/F | 0.43 | 0.41 | 23% | 0.21, 0.59 |
| CLwb/F ∼ Qwb/F | 0.62 | 0.66 | 18% | 0.40, 0.87 |
| Between occasion variability | ||||
| F (CV %) | 23 | 22 | 7% | 20, 25 |
| ka (CV %) | 120 | 122 | 7% | 107, 140 |
| Residual error | ||||
| Proportional error (%) | 14.9 | 14.9 | 4% | 13.6, 16.3 |
CI, confidence interval; CLwb/F, apparent whole blood clearance; CV, coefficient of variation; CYP3A5, cytochrome P450 3A5; Fday2, the increase in F the day after transplantation; FFM, fat free mass; HCT, haematocrit; ka, absorption rate constant; Predmax, maximum change in F with increasing prednisolone dose; Pred50, the prednisolone dose with half maximum effect on F; Q/Fwb, apparent whole blood intercompartmental clearance; RSE, relative standard error; tlag, absorption lag time; V1/Fwb, apparent whole blood central volume of distribution; V2/Fwb, apparent whole blood peripheral volume of distribution.
Standardized to CYP3A5 non-expresser with haematocrit of 45% and fat free mass of 60 kg not receiving prednisolone.
95% confidence interval generated from the 2.5th to 97.5th percentiles obtained from 500 non-parametric bootstraps replicates.
CYP3A5 expressers included patients expressing one or two *1 alleles. The disposition parameters are presented standardized to a haematocrit of 45%, generated by dividing the plasma concentration based parameters in the model by the expected blood:plasma concentration ratio at a haematocrit of 45%. The original model was as follows:
CLp/F = 811 × (FFM/60)3/4 × 1.30 (If CYP3A5 expresser) l h−1
V1p/F = 6290 × FFM/60 l
Qp/F = 1200 × (FFM/60) l h−1
V2p/F = 32100 × FFM/60 l
F = 1 × [1 – (0.67 × Prednisolone dose)/(35 mg + Prednisolone dose)] × 2.68 (If first day post-transplant) × 0.82 (If CYP3A5 expresser)
Crbc = fHCT × Cp × 418/(3.8 + Cp)
Cwb = Cp + Crbc,
where CLp/F is the apparent plasma clearance, V1p/F is the apparent plasma central volume of distribution, Qp/F is the apparent plasma intercompartmental clearance, V2p/F is the apparent plasma peripheral volume of distribution, FFM is the fat free mass, F is the bioavailability relative to 1, Crbc is the tacrolimus concentration in red blood cells, Cp is the tacrolimus plasma concentration, Cwb is the tacrolimus whole blood concentration and fHCT is the haematocrit fraction.