Table 4. Pharmacokinetic parameters for sunitinib, its active metabolite (SU12662), and total drug (sunitinib plus SU12662), and gemcitabine and its main metabolite (dFdU) in patients treated on Schedule 2/1 (subjects with paired observations only).
| Analyte | Parameter | Mean (CV%) sunitinib alone, C1D15 (median) | Mean (CV%) gemcitabine alone, C1D1 (median) | Mean (CV%) sunitinib plus gemcitabine, C1D8 (Median) | Geometric mean ratio (combination vs sunitinib alone) |
|---|---|---|---|---|---|
|
All dose cohorts combined (n=32)a | |||||
| Sunitinib | Cmax, ng ml−1 | 63.6 (43) (56.6) | — | 71.5 (58) (60.0) | 0.92 |
| AUC24, ng h ml−1 | 1241 (46) (1113) | — | 1445 (52) (1282) | 0.87 | |
| Tmax, hb | 4.0 (0.0–9.0) | — | 7.0 (3.0–24.0) | N/A | |
| CL/F, l h−1 | 47.0 (37) (44.9) | — | 41.4 (37) (39.0) | 1.14 | |
| SU12662 | Cmax, ng ml−1 | 19.4 (51) (15.7) | — | 27.5 (68) (20.6) | 0.74 |
| AUC24, ng h ml−1 | 411 (51) (333) | — | 596 (71) (453) | 0.73 | |
| |
Tmax, hb |
4.0 (0.0–24.0) |
— |
4.0 (0.0–24.0) |
NA |
| Total drug (sunitinib+SU12662) | Cmax, ng ml−1 | 82.4 (38) (71.0) | — | 98.3 (53) (82.2) | 0.87 |
| AUC24, ng h ml−1 | 1653 (40) (1485) | — | 2043 (49) (1736) | 0.83 | |
| |
Tmax, hb |
4.0 (0.0–24.0) |
— |
7.0 (3.0–24.0) |
NA |
|
All dose cohorts combined (n=30)a | |||||
| Gemcitabine | Cmax, μg ml−1 | — | 20.9 (25) (20.7) | 25.0 (36) (24.4) | 1.16 |
| AUC∞, μg h ml−1 | — | 10.5 (30) (10.5) | 12.6 (36) (12.8) | 1.18 | |
| Tmax, hb | — | 0.25 (0.3–0.5) | 0.25 (0.3–0.5) | NA | |
| CL, l h−1 | — | 262 (38) (240) | 225 (44) (203) | 0.84 | |
| t1/2, h | — | 0.26 (20) (0.26) | 0.29 (23) (0.27) | NA | |
| dFdU | Cmax, μg ml−1 | — | 45.3 (17) (44.9) | 50.8 (22) (49.7) | 1.11 |
| AUC24, μg h ml−1 | — | 268 (29) (248) | 272 (31) (254) | 1.01 | |
| Tmax, hb | — | 0.5 (0.3–1.5) | 0.5 (0.5–1.5) | NA | |
Abbreviations: AUC24/∞=area under the plasma concentration versus time curve from time zero to 24 h/infinity; C=cycle; CL=clearance; CL/F=clearance at steady state after oral administration; Cmax=maximum plasma concentration; CV%=coefficient of variation percentage; D=day; NA=not available; Tmax=time to maximum plasma concentration, t1/2=terminal phase half life.
a
For the combined cohorts (Schedule 2/1, dose levels 1–6; Table 1), dose correction to sunitinib 50 mg and gemcitabine 1250 mg m−2 was performed.
b
Tmax: median (min, max).