Clinically observed and PBPK model–predicted pharmacokinetic parameters of crizotinib in healthy subjects following a single oral administration of crizotinib with and without multiple coadministration of ketoconazole 200 mg twice daily or rifampin 600 mg once daily
Data are expressed as geometric mean with percent coefficient of variation (CV%) in parentheses (n = 15 for the observed; n = 15 per group × 6 groups for the predicted).
| Interacting Drug | Control Group | Treatment Group | Fold Increasea | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Cmax | AUC0–∞ | t1/2,z | Cmax | AUC0–∞ | t1/2,z | CmaxR | AUCR | ||
| ng/ml | ng⋅h/ml | h | ng/ml | ng⋅h/ml | h | ratio | ratio | ||
| Ketoconazole | Observed | 66 (35) | 1260 (25) | 37 (12) | 94 (20) | 3986 (25) | 55 (11) | 1.4 | 3.2 |
| Predicted (on)b | 57 (35) | 1422 (47) | 51 (22) | 89 (32) | 4896 (41) | 113 (30) | 1.6 | 3.4 | |
| P/Oc | 0.87 | 1.1 | 1.4 | 0.95 | 1.2 | 2.1 | 1.1 | 1.1 | |
| Predicted (off)b | 56 (35) | 1335 (45) | 50 (21) | 89 (32) | 4764 (41) | 111 (29) | 1.6 | 3.6 | |
| On/Offd | 1.0 | 1.1 | 1.0 | 1.0 | 1.0 | 1.0 | 0.99 | 0.96 | |
| Rifampin | Observed | 102 (33) | 2192 (27) | 33 (21) | 32 (33) | 397 (26) | 48 (12) | 0.31 | 0.18 |
| Predicted (on)b | 95 (35) | 2499 (48) | 55 (23) | 29 (56) | 369 (69) | 33 (16) | 0.31 | 0.15 | |
| P/Oc | 0.93 | 1.1 | 1.7 | 0.91 | 0.93 | 0.69 | 0.97 | 0.82 | |
| Predicted (off)b | 94 (35) | 2256 (45) | 53 (22) | 28 (59) | 343 (69) | 33 (16) | 0.30 | 0.15 | |
| On/Offd | 1.0 | 1.1 | 1.0 | 1.0 | 1.1 | 1.0 | 1.0 | 0.97 | |
↵a Fold-increase in Cmax and AUC0–∞ of the treatment group (crizotinib with ketoconazole or rifampin) relative to control group (crizotinib alone).
↵b The simulation results with (on) and without (off) crizotinib DDI parameters.
↵c Ratio of the predicted to observed results.
↵d Ratio of the predicted results on over off.