Table 2.
Prediction of P-gp inhibition in 26 clinical DDI studies with digoxin as a victim drug, using FDA criteria and P-gp IC50 values from rhodamine 123 accumulation or digoxin bidirectional transport [41] assays.
| Perpetrator | [I1]; [I2] (µM) 1,2 | AUCi/AUC 2,3 | Cmaxi/Cmax 2,4 | Clinical Relevance 5 | P-gp Inhibition Prediction (FDA Criteria 6) | |
|---|---|---|---|---|---|---|
| Rhodamine 123 IC50 | Digoxin IC50 2 | |||||
| Carvelidol | 0.13; 62 | 1.24 | 1.00 | − | + (FP) 7 | + (FP) |
| Diltiazem | 0.7; 868 | 1.24 | 1.24 | − | + (FP) | + (FP) |
| Mibefradil | 0.8; 404 | 1.08 | 1.22 | − | + (FP) | + (FP) |
| Nicardipine | 0.18; 250 | 1.06 | 1.06 | − | + (FP) | + (FP) |
| Nitrendipine | 0.015; 111 | 1.09 | 1.22 | − | − (TN) 8 | − (TN) |
| Troglitazone | 3.62; 3,624 | 1.04 | 1.05 | − | + (FP) | + (FP) |
| Amiodarone | 2.49; 2479 | 1.63 | 1.72 | + | + (TP) 9 | + (TP) |
| Amiodarone | 2.20; 4959 | 1.68 | 1.84 | + | + (TP) | + (TP) |
| Carvelidol | 0.52; 246 | 1.2 | 1.60 | + | + (TP) | + (TP) |
| Carvelidol | 0.13; 62 | 1.56 | 1.38 | + | +(TP) | +(TP) |
| Cyclosporin A | 2.8; 1167 | NR 10 | 1.44 | + | + (TP) | + (TP) |
| Diltiazem | 0.7; 579 | 1.44 | 1.38 | + | + (TP) | + (TP) |
| Diltiazem | 0.17; 579 | 1.51 | 1.37 | + | +(TP) | +(TP) |
| Felodipine | 0.03; 104 | 1.18 | 1.34 | + | − (FN)11 | + (TP) |
| Isradipine | 0.02; 54 | 1.11 | 1.26 | + | − (FN) | − (FN) |
| Itraconazole | 0.95; 1134 | 1.68 | 1.34 | + | − (FN) | + (TP) |
| Mibefradil | 2.42; 1211 | 1.31 | 1.41 | + | + (TP) | + (TP) |
| Mibefradil | 1.61; 807 | 1.07 | 1.25 | + | + (TP) | + (TP) |
| Nitrendipine | 0.03; 222 | 1.15 | 1.57 | + | − (FN) | + (TP) |
| Quinidine | 3.54; 3397 | 1.76 | 1.75 | + | + (TP) | + (TP) |
| Quinidine | 5.10; 2466 | 2.65 | NR | + | + (TP) | + (TP) |
| Quinidine | 4.5; 2466 | NR | 1.44 | + | + (TP) | + (TP) |
| Verapamil | 1.2; 704 | 1.51 | 1.44 | + | + (TP) | + (TP) |
| Verapamil | 0.026; 704 | NR | 1.53 | + | + (TP) | + (TP) |
| Verapamil | 0.058; 1056 | NR | 1.61 | + | + (TP) | + (TP) |
| Verapamil | 0.033; 704 | NR | 1.77 | + | + (TP) | + (TP) |
1 [I1]: total plasma concentration; [I2]: gut concentration; 2 data from Poirier et al. [41]; 3 area under the curve in the presence (AUCi) or absence (AUC) of P-gp inhibitor. 4 peak plasma concentration in the presence (Cmaxi) or absence (Cmax) of P-gp inhibitor. 5 clinical relevance: AUCi/AUC ≥ 1.25 and/or Cmaxi/Cmax ≥ 1.25; 6 FDA criteria: [I1]/IC50 > 0.1 and/or [I2]/IC50 > 10; 7 FP: false positive; 8 TN: true negative; 9 TP: true positive; 10 NR: not reported; 11 FN: false negative.