Groupa | PBPK Model | Jmaxb | Kic | Analysisd | Cmax | AUC | CmaxRe | AUCRe |
---|---|---|---|---|---|---|---|---|
SF | μM | ng/ml | ng⋅h/ml | ratio | ratio | |||
Control | − | − | − | Obs | 114 (35) | 2330 (35) | − | − |
Fa | − | − | Pred | 84 (41) | 3013 (64) | − | − | |
P/O | 0.74 | 1.29 | − | − | ||||
ADAM | − | − | Pred | 153 (48) | 3606 (64) | − | − | |
P/O | 1.34 | 1.55 | − | − | ||||
1 | − | Pred | 136 (49) | 3316 (66) | − | − | ||
P/O | 1.20 | 1.42 | − | − | ||||
4 | − | Pred | 109 (53) | 2738 (71) | − | − | ||
P/O | 0.95 | 1.18 | − | − | ||||
Test | − | − | − | Obs | 326 (24) | 15,200 (29) | 2.9 | 6.5 |
Fa | − | − | Pred | 228 (32) | 13,311 (69) | 2.8 (2.5–3.1) | 4.2 (3.3–5.2) | |
P/O | 0.70 | 0.88 | 0.97 | 0.66 | ||||
ADAM | 4 | − | Pred | 226 (43) | 10,639 (61) | 2.1 (2.0–2.3) | 4.0 (3.1–4.9) | |
P/O | 0.69 | 0.70 | 0.72 | 0.60 | ||||
4 | 0.2 | Pred | 272 (40) | 12,127 (57) | 2.6 (2.4–2.8) | 4.7 (3.7–5.7) | ||
P/O | 0.83 | 0.80 | 0.87 | 0.70 |
−, not applicable or not calculated.
↵a Bosutinib 500 mg without and with ketoconazole 400 mg once daily (control and test groups, respectively).
↵b Predicted in vitro-to-in vivo scaling factor (SF) for intestinal P-gp Jmax.
↵c Predicted ketoconazole Ki value for intestinal P-gp.
↵d Obs, observed; Pred, predicted; P/O, ratios of predicted to observed value.
↵e Ratios of Cmax and AUC in test group relative to control group.