Table 2.
Parameter estimates of the base and final dabrafenib/hydroxy-dabrafenib pharmacokinetic model and bootstrap results.
| Parameters | Base DAB/OHD Model | Final DAB/OHD Model | Bootstrap (n = 500 Samples) |
|||
|---|---|---|---|---|---|---|
| Estimate | RSE (%) | Estimate | RSE (%) | Median | PI95% | |
| CL/F (L/h) | 17.7 | 6.4 | 19.3 | 7.5 | 19.2 | 16.0–22.4 |
| V2/F (L) | 39.5 | 13.1 | 39.1 | 13.7 | 38.3 | 26.9–52.1 |
| ka (1/h) | 1.8 fixed | 1.8 fixed | 1.8 fixed | |||
| Q/F (L/h) | 3.85 | 23.0 | 3.40 | 21.5 | 3.32 | 1.59–6.60 |
| V4/F (L) | 19.6 | 19.6 | 18.7 | 20.1 | 18.7 | 12.5–39.8 |
| CLm/F (L/h) | 22.8 | 5.8 | 23.2 | 5.9 | 22.9 | 19.8–25.9 |
| V3/F (L) | 5.23 | 26.2 | 5.11 | 30.5 | 4.99 | 0.385–9.03 |
| Qm/F (L/h) | 7.39 | 23.7 | 7.21 | 22.3 | 7.02 | 4.42–12.1 |
| V5/F (L) | 25.7 | 20.4 | 27.1 | 23.9 | 24.7 | 16.1–45.8 |
| Tlag (h) | 0.50 | 0.20 | 0.499 | 0.2 | 0.499 | 0.295–0.578 |
| θage/(CL/F) | - | - | −0.536 | 28.4 | −0.499 | −0.827−0.215 |
| θage/(CLm/F) | - | - | −0.589 | 33.6 | −0.543 | −0.879−0.168 |
| θsex/(CL/F) | - | - | 0.832 | 6.4 | 0.829 | 0.732–0.932 |
| IIVCL/F (%) | 21.9 | 17.2 | 16.0 | 21.9 | 14.4 | 5.83–20.9 |
| IIVV2/F (%) | 43.0 | 18.1 | 50.8 | 20.0 | 69.4 | 44.3–88.9 |
| IIVCLm/F (%) | 26.8 | 11.9 | 24.0 | 14.4 | 21.8 | 15.5–28.5 |
| IIVV3/F (%) | 84.0 | 47.5 | 47.5 | 51.5 | 82.0 | 15.9–278 |
| IOV (%) | 17.2 | 11.8 | 17.4 | 12.0 | 17.0 | 13.1–20.3 |
| RUV of DAB (%) | 49.2 | 6.4 | 48.7 | 6.6 | 48.2 | 41.8–54.6 |
| RUV of OHD (%) | 53.1 | 6.4 | 53.1 | 6.3 | 52.7 | 46.2–59.1 |
| RUVcorr (%) | 87.3 | 11.5 | 87.0 | 2.1 | 87.3 | 80.4–92.1 |
PI95%; 95% percentile interval; CL/F, apparent clearance of DAB; CLm/F, apparent clearance of OHD; IIV, interindividual variability defined as coefficient of variation (%); IOV, inter-occasion variability on CL/F defined as coefficient of variation (%); ka, first-order absorption rate constant; Q/F, inter-compartment clearance of DAB; Qm/F, inter-compartment clearance of OHD; RSE, relative standard error defined as SE/estimate, with SE directly retrieved from NONMEM; RUV, residual unexplained variability; RUVcorr, correlation between the proportional error components; Tlag, lag time, V2/F, apparent central volume of distribution of DAB; V3/F, apparent central volume of distribution of OHD; V4/F, apparent peripheral volume of distribution of DAB; V5/F, apparent peripheral volume of distribution of OHD; θage/(CL/F), Age effect on CL/F; θage/(CLm/F), Age effect on CLm/F; θsex/(CL/F), Sex effect on CL/F. Final model equations for individual CL/F and CLm/F: CL_ind/F = CL/F × (1 + θage/(CL/F) × (AGE-MAGE)/MAGE) × (θsex/(CL/F)Sex) × exp(IIVCL/F_ind). CLm_ind/F = CLm/F × (1 + θage/(CLm/F) × (AGE-MAGE)/MAGE) × exp(IIVCLm/F_ind). with MAGE = 61.2 years, median AGE value in the study population; Sex being 0/1 for man/woman, and the rest as previously defined.