Means and 95% confidence intervals of parameters in human, monkey, and rat PBPK models estimated by fitting in vivo data, and retrospective ratios among different species
| Parameter | Human | Monkey | Rat | Monkey to Human Ratio | Rat to Human Ratio |
|---|---|---|---|---|---|
| ET koff (h−1) | 1.61 × 104 (7200, 3.4 × 104) | 1039 (240, 1.1 × 104) | 47.9 (4.78, 505) | 0.0645 | 2.98 × 10−3 |
| ET total concentration (nM) | 2750 (1400, 4900) | 2310 (1400, 4100) | 2251 (968, 3890) | 0.840 | 0.819 |
| CLliver,pass (l/h) | 23.9 (13, 44) | 4.86 (2.8, 8.5) | 0.0322 (8.98 × 10−4, 0.619) | 0.203 | 1.35 × 10−3 |
| kliver,uptake (nmol/h) | 4.78 × 106 (3.8 × 106, 6.5 × 106) | 6.25 × 105 (4.6 × 105, 9.0 × 105) | 1.12 × 105 (8.9 × 104, 3.4 × 105) | 0.131 | 0.0234 |
| kliver,metabolism (nmol/h) | 1.00 × 106 (8.0 × 105, 1.3 × 106) | 1.67 × 105 (1.5 × 105, 1.8 × 105) | 1.50 × 103 | 0.167 | |
| kliver,efflux (nmol/h) | 6.00 × 104 | 0.539 | 5.55 | ||
| Km,liver,efflux (nM) | 1.48 × 106 | 3.5 × 104 | 93.9 | ||
| Nonliver tissue Kpu scaler | 1 (fixed) | 1.47 (0.86, 2.3) | 4.53 (<7.11) | 1.47 | 4.53 |
| Body weight (kg) | 70.0 (fixed) | 6.20 (fixed) | 0.250 (fixed) | 0.0886 | 3.57 × 10−3 |
| Liver tissue weight (kg) | 1.69 (fixed) | 0.167 (fixed) | 0.0103 (fixed) | 0.0988 | 6.09 × 10−3 |
a Because Km,liver,metabolism for rats is not available from in vitro studies, it is estimated by fitting in vivo PK data with other parameters. The mean is estimated to be 6430 nM but with a high uncertainty.
Medians and confidence intervals are not provided for the parameters with high uncertainty (i.e., the range of the approximated confidence interval is greater than 20 magnitude). The globally optimized value is provided instead. Values for humans were generated in part 1 of this work (Li et al., 2018); whereas values for rats and monkeys are estimated in this study.