Median values and 95% CIs of optimized parameters in the bosentan PBPK model
Values and CIs were estimated by fitting clinical data.
| Parameter | Median (95% CI) |
|---|---|
| ET koff (h−1) | 1.61 × 104 (7200, 3.4 × 104) |
| ET total concentration (nM) | 2750 (1400, 4900) |
| CLliver,pass (l/h) | 23.9 (13, 44) |
| kliver,uptake (nmol/h) | 4.78 × 106 (3.8 × 106, 6.5 × 106) |
| kliver,metabolism (nmol/h) | 1.00 × 106 (8.0 × 105, 1.3 × 106) |
| kliver,efflux (nmol/h) | 6.00 × 104 |
| Km,liver,efflux (nM) | 1.48 × 106 |
| ka (h−1) | 0.932 (0.81, 1.3) |
| ka (meal) (h−1) | 0.759 (0.64, 1.1) |
| fu,enterocyte | 0.964 (0.50, 1.0) |
| CLenterocyte,pass (l/h) | 2.31 × 10−5 (<1.1 × 10−4) |
| CLenterocyte,efflux (l/h) | 6.80 × 10−5 (<1.1 × 10−4) |
| Clinical induction Emax | 1.36 (1.0, 1.7) |
| Tadalafil FaFg with bosentan | 0.868 (0.70, 1.0) |
| S-warfarin FaFg with bosentan | 1.10 (0.99, 1.2) |
| R-warfarin FaFg with bosentan | 1.00 (0.83, 1.3) |
Medians and CIs are not provided for the parameters with high uncertainty (i.e., the range of the approximated CI is greater than 20 magnitude). The globally optimized values (and upper bound if possible) are provided instead.