Table 4.
Observed and simulated AUCplasma (mean and 95% prediction interval)
| Simulations | ||||
|---|---|---|---|---|
| Observations | Method 1 | Method 2 | ||
| Bosentan | Healthy | 11957 (1803, 23035) | 8313 | 8313 |
| CP-A | 10781 (1577, 20931) | 13389 (4870, 45698) | 12825 (6811, 32887) | |
| Olmesartan | Healthy | 5964 (3657, 8271) | 4811 | 4811 |
| CP-A | 6780 (0, 15640) | 5795 (2698, 12648) | 5294 (3457, 10907) | |
| CP-B | 6972 (4093, 9851) | 4965 (2256, 13245) | 7394 (3686, 17451) | |
| Repaglinide | Healthy | 92 (0, 245) | 62 | 62 |
| CP-B | 369 (0, 903) | 173 (32, 694) | 303 (129, 910) | |
| Telmisartan | Healthy | 471 (0, 1282) | 392 | 392 |
| CP-A | 1290 (0, 4060) | 785 (49, 3079) | 766 (83, 3762) | |
| Valsartan | Healthy | 21200 (6309, 36091) | 21640 | 21640 |
| CP-A | 46800 (25698, 67902) | 26817 (11829, 52989) | 25568 (15995, 47824) | |
| CP-B | 45400 (37827, 52973) | 25436 (10618, 53145) | 39796 (19739, 72470) | |
AUCs of healthy individuals are generated using values given in Table 1.
95% prediction intervals of observations are estimated using reported standard deviations and t statistic, and prediction intervals of simulations are approximated using 2.5 and 97.5 percentile of 1000 simulations.
Method 1 represents 1000 simulations with mRNA-derived Rtransporter, contributions of individual transporters made to total uptake are randomly generated from a uniform distribution, and other parameters listed in Table 3 are randomly generated using reported mean and standard deviations.
Method 2 represents the single simulations with fitted Rtransporter, and other parameters listed in Table 3 fixed at their mean values. The prediction intervals are approximated using the same method as Method 1 except that Rtransporter were prepared with residual bootstrap results.
For bosentan, the observed AUCs are reported as geometric mean values, as are the simulated AUCs. For the other four compounds, the observed AUC are reported as arithmetic mean values, as are the simulated AUCs.
For bosentan and telmisartan, the observed AUCs are reported as AUC0 – ∞, as are the simulations. For olmesartan, repaglinide, and valsartan, the observed AUCs are reported up to 96, 48, and 36 hours, respectively, as are the simulations.