Clinically observed and PBPK model-predicted pharmacokinetic parameters of bosutinib in humans following a single intravenous and oral administration of bosutinib
Data are expressed as geometric mean with percent coefficient of variation (CV%) in parentheses (n = 13–14 for the observed; n = 6 per group × 6 groups for the predicted) except for median tmax with minimal to maximal values.
| Dose | PBPK Modela | Jmaxb | Analysisc | Cmax | tmax | AUC |
|---|---|---|---|---|---|---|
| mg | SF | ng/ml | h | ng∙h/ml | ||
| 120 | − | − | Obs | 347 (28) | 1 (1–1) | 1920 (26) |
| IV-1 | − | Pred | 662 (14) | 1 (1–1) | 2934 (35) | |
| P/O | 1.91 | − | 1.53 | |||
| IV-2 | − | Pred | 563 (13) | 1 (1–1) | 2128 (28) | |
| P/O | 1.62 | — | 1.11 | |||
| 500 | − | − | Obs | 109 (43) | 6 (2–8) | 2736 (44) |
| Fa-1 | − | Pred | 36 (55) | 4 (3–7) | 1012 (77) | |
| P/O | 0.33 | − | 0.37 | |||
| Fa-2 | − | Pred | 83 (47) | 4 (3–7) | 2374 (46) | |
| P/O | 0.76 | − | 0.87 | |||
| ADAM | − | Pred | 138 (48) | 5 (2–11) | 3038 (64) | |
| P/O | 1.27 | – | 1.11 | |||
| 1 | Pred | 123 (49) | 5 (2–15) | 2770 (66) | ||
| P/O | 1.12 | – | 1.01 | |||
| 2 | Pred | 112 (51) | 5 (2–17) | 2560 (68) | ||
| P/O | 1.03 | – | 0.94 | |||
| 4 | Pred | 96 (53) | 5 (2–20) | 2235 (71) | ||
| P/O | 0.88 | – | 0.82 |
−, not application or not calculated.
↵a CLint = 300 μl/min per milligram protein and Vss = 15 l/kg (IV-1) or CLint = 560 μl/min per milligram protein and Vss = 28 l/kg (IV-2, Fa-1, Fa-2, and ADAM) with fu,gut = 1 (Fa-1) or 0.063 (Fa-2 and ADAM).
↵b Predicted in vitro-to-in vivo scaling factor (SF) for intestinal P-gp Jmax.
↵c Obs, observed; Pred, predicted; P/O, ratios of predicted to observed value.