Predicted net DDI vs. that observed and associated geometric fold error assuming total plasma concentrations and interaction in the liver only ( eq. 9 ) or interaction in the liver plus intestine ( eq. 16 ), using all in vitro data (reversible inhibition, time-dependent inactivation, and induction)
Precipitant | Range of DDI (Observed) | [I]H | AUC′/AUC (Predicted) ([I]H) | GFE | [I]G | AUC′/AUC (Predicted) ([I]H + [I]G) | GFE |
|---|---|---|---|---|---|---|---|
| μM | μM | ||||||
| Avasimibe | 0.27 | 0.50 | 0.63 | 2.3 | 12.1 | 1.4 | 5.4 |
| Avasimibe | 0.06 | 1.5 | 0.60 | 10 | 181 | 2.0 | 33 |
| Azithromycin | 0.87–1.3 | 0.27 | 1.2 | 1.1 | 80.8 | 2.1 | 1.9 |
| Azithromycin | 1.0 | 0.27 | 1.2 | 1.2 | 40.4 | 1.6 | 1.6 |
| Bosentan | 0.66 | 2.6 | 0.09 | 7.4 | 25.3 | 0.12 | 5.5 |
| Carbamazepine | 0.26 | 34 | 0.09 | 2.8 | 154 | 0.07 | 3.9 |
| Cimetidine | 1–2.2 | 3.3 | 1.1 | 1.4 | 144 | 1.7 | 1.1 |
| Clarithromycin | 3.6 | 2.4 | 7.8 | 2.2 | 40.4 | 14 | 3.8 |
| Clarithromycin | 5.5–8.4 | 3.0 | 8.6 | 1.2 | 80.9 | 15 | 2.1 |
| Clarithromycin | 5.3 | 2.2 | 7.5 | 1.4 | 80.9 | 10 | 1.9 |
| Clarithromycin | 10 | 4.8 | 10 | 1.0 | 80.9 | 15 | 1.5 |
| Cyclosporine | 8.0 | 1.9 | 8.2 | 1.0 | 26.8 | 12 | 1.6 |
| Cyclosporine | 2.6 | 0.58 | 4.5 | 1.8 | 23.8 | 6.8 | 2.7 |
| Diltiazem | 3.8 | 0.14 | 6.2 | 1.6 | 17.5 | 11 | 2.9 |
| Diltiazem | 3.0 | 0.14 | 6.2 | 2.1 | 17.5 | 8.0 | 2.7 |
| Diltiazem | 4.8 | 0.27 | 8.4 | 1.7 | 35.0 | 13 | 2.6 |
| Diltiazem | 2.3–3.4 | 0.14 | 6.2 | 2.2 | 17.5 | 8.3 | 3.0 |
| Erythromycin | 3.3 | 0.44 | 3.0 | 1.1 | 33.0 | 5.3 | 1.6 |
| Erythromycin | 3.8–4.4 | 0.95 | 4.7 | 1.2 | 82.4 | 8.3 | 2.0 |
| Erythromycin | 3.8 | 0.95 | 4.7 | 1.2 | 82.4 | 6.3 | 1.7 |
| Erythromycin | 6.2 | 0.95 | 4.7 | 1.3 | 82.4 | 7.2 | 1.2 |
| Erythromycin | 2.1 | 3.3 | 8.6 | 4.1 | 54.9 | 11 | 5.5 |
| Ethinyl estradiol | 1.1–1.2 | 0.01 | 1.0 | 1.1 | 20.4 | 1.7 | 1.5 |
| Fluconazole | 3.6 | 7.2 | 1.9 | 1.9 | 59.3 | 3.1 | 1.2 |
| Fluconazole | 3.6–4.9 | 29 | 4.1 | 1.1 | 158 | 7 | 1.6 |
| Fluconazole | 2.7 | 22 | 3.5 | 1.3 | 79.1 | 4.3 | 1.6 |
| Fluconazole | 2.1–4.4 | 7.2 | 1.9 | 1.7 | 39.5 | 2.4 | 1.3 |
| Fluoxetine | 0.87 | 0.36 | 2.5 | 2.8 | 21.0 | 5.4 | 6.2 |
| Fluoxetine | 1.0 | 0.36 | 2.5 | 2.5 | 21.0 | 4.1 | 4.1 |
| Itraconazole | 6.2–10.8 | 0.27 | 9.7 | 1.2 | 34.3 | 17 | 2.2 |
| Itraconazole | 10 | 0.27 | 9.7 | 1.0 | 34.3 | 15 | 1.5 |
| Itraconazole | 3.1–4.5 | 0.27 | 9.7 | 2.5 | 34.3 | 13 | 3.3 |
| Ketoconazole | 14 | 5.4 | 14 | 1.0 | 45.6 | 24 | 1.8 |
| Ketoconazole | 5.2–8.7 | 1.9 | 13 | 1.9 | 45.6 | 23 | 3.4 |
| Ketoconazole | 9.5–15.9 | 2.8 | 14 | 1.1 | 91.1 | 20 | 1.6 |
| Ketoconazole | 9.2–22.4 | 5.4 | 14 | 1.1 | 45.6 | 19 | 1.2 |
| Mibefradil | 8.9 | 1.2 | 14 | 1.5 | 24.4 | 24 | 2.7 |
| Mibefradil | 8.4 | 1.2 | 14 | 1.6 | 12.2 | 19 | 2.2 |
| Modafinil | 0.42 | 49 | 0.19 | 2.2 | 133 | 0.26 | 1.6 |
| Nafcillin | 0.37 | 44 | 0.24 | 1.5 | 133 | 0.37 | 1.0 |
| Nelfinavir | 6.1 | 7.1 | 12 | 2.0 | 246 | 20 | 3.3 |
| Nifedipine | 1.0 | 0.29 | 0.71 | 1.5 | 21.0 | 0.42 | 2.5 |
| Phenobarbital | 0.39 | 52 | 0.10 | 3.9 | 52.1 | 0.13 | 3.0 |
| Phenytoin | 0.06 | 70 | 0.11 | 1.8 | 71.9 | 0.10 | 1.6 |
| Pioglitazone | 0.98 | 2.8 | 2.2 | 2.2 | 13.9 | 5.4 | 5.5 |
| Pleconaril | 0.65 | 2.4 | 0.17 | 3.9 | 122 | 0.05 | 12 |
| Raloxifene | 1.0 | 0.001 | 1.0 | 1.0 | 16.1 | 1.8 | 1.8 |
| Rifampin | 0.016–0.041 | 12 | 0.09 | 3.3 | 88.2 | 0.08 | 2.8 |
| Rifampin | 0.08 | 12 | 0.09 | 1.1 | 88.2 | 0.11 | 1.4 |
| Rifampin | 0.09–0.14 | 12 | 0.09 | 1.3 | 88.2 | 0.09 | 1.3 |
| Rifampin | 0.05 | 12 | 0.09 | 1.8 | 88.2 | 0.11 | 2.1 |
| Ritonavir | 20.4–40.7 | 12 | 14 | 1.9 | 33.6 | 19 | 1.4 |
| Rosiglitazone | 0.88 | 0.34 | 1.8 | 2.0 | 2.04 | 2.6 | 2.9 |
| Roxithromycin | 1.5 | 5.1 | 4.5 | 3.1 | 43.4 | 8 | 5.3 |
| Saquinavir | 5.2 | 0.43 | 12 | 2.3 | 216 | 23 | 4.4 |
| Troglitazone | 0.62 | 4.8 | 13 | 21 | 110 | 21 | 34 |
| Troleandomycin | 3.8 | 0.15 | 2.0 | 1.9 | 149 | 4.7 | 1.3 |
| Verapamil | 2.9 | 0.22 | 3.3 | 1.2 | 21.3 | 10 | 3.5 |
| Verapamil | 4.7 | 0.22 | 3.3 | 1.4 | 21.3 | 9 | 1.9 |
| Geometric mean fold error |
|
|
|
1.8
|
|
|
2.5
|
Values highlighted in bold are above 2-fold